rs199573929

Positions:

• chr2-73448563-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001378454.1(ALMS1):​c.2036A>G​(p.Tyr679Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,872 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:6
• Conservation: PhyloP100: -0.105

Genes affected

ALMS1 (HGNC:428): (ALMS1 centrosome and basal body associated protein) This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015712231).
• BP6: Variant 2-73448563-A-G is Benign according to our data. Variant chr2-73448563-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=7}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00149 (227/152150) while in subpopulation SAS AF= 0.00269 (13/4826). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 102 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.2036A>G	p.Tyr679Cys	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.2036A>G	p.Tyr679Cys	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.2036A>G	p.Tyr679Cys	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00157 AC: 390 AN: 248830 Hom.: 0 AF XY: 0.00173 AC XY: 234 AN XY: 134962

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.000835

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00251 AC: 3669 AN: 1461722 Hom.: 7 Cov.: 82 AF XY: 0.00253 AC XY: 1839 AN XY: 727170

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00284

Gnomad4 FIN exome AF: 0.000636

Gnomad4 NFE exome AF: 0.00292

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74380

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00148

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00279 AC: 23

ExAC AF: 0.00163 AC: 197

EpiCase AF: 0.00180

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Alstrom syndrome Uncertain:4 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Apr 16, 2021	The p.Tyr680Cys (also referred to as p.Tyr678Cys) variant in the ALMS1 gene has been previously reported in 2 unrelated individuals, 1 individual was heterozygous without a second variant identified, and 1 individual was compound heterozygous but had a phenotype inconsistent with Alstrom syndrome (Campbell et al., 2018; Celestino-Soper et al., 2015). This variant has also been identified in 76/30,598 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is greater than would be expected to be disease-causing for Alstrom syndrome. Previously reported disease-causing variants in ALMS1 have been primarily truncating variants, whereas this variant results in a single amino acid substitution. The significance of this type of variation in the ALMS1 gene is currently unclear. Computational tools predict that the p.Tyr680Cys variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Tyr680Cys variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs199573929 in Alstrom syndrome yet. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2016	- -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 05, 2016	Given its frequency in a large number of controls, no case data, and the autosomal recessive inheritance pattern of the associated disease, we consider this variant a variant of uncertain significance likely benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has not been seen in any cases of atrial fibrillation or ALMS1-related disease. Testing for our patient was performed at Invitae. The ALMS1 gene is associated with autosomal recessive Alström syndrome. Alström syndrome includes cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. Our patient was only found to have one variant in this gene and does not have a phenotype consistent with this condition. This sequence change replaces tyrosine with cysteine at codon 680 of the ALMS1 protein (p.Tyr680Cys). The tyrosine residue is weakly conserved and there is a large physicochemical di erence between tyrosine and cysteine. Algorithms developed to predict the e ect of missense changes on protein structure and function do not agree on the potential impact of this missense change. The variant is present in 422 of 140,893 (MAF = 0.15%) total individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically, the variant is present in 292 of 63,046 European Non-Finnish individuals (MAF= 0.23%). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	Reported in a patient with dilated cardiomyopathy in published literature (Burstein et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID 210126; ClinVar); This variant is associated with the following publications: (PMID: 32746448) -

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2023	Variant summary: ALMS1 c.2033A>G/p.Tyr678Cys (also known as c.2039A>G/p.Tyr680Cys) results in a non-conservative amino acid change located in the Alstrom syndrome repeat region (IPR040972) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248830 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.12 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2033A>G has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=5, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2018	p.Tyr680Cys in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 0.25% (76/30778) South Asian and 0. 23% (293/125986) European chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org; dbSNP rs199573929). Tyrosine (Tyr) at positi on 680 is not highly conserved in mammals and evolutionary distant species, with one mammal (golden hamster) carrying a cystine (Cys) at this position, supporti ng that this change at this position may be tolerated. Additional computational computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein. ACMG/AMP Criteria applied: BS1_P; BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2015	- -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jun 29, 2018

ACMG criteria: BP1, BS1 (0.2% MAF in gnomAD SA and ENF) [REVEL 0.191, PP3 (3), BP4 (6)= conflicting evidence, not using]= likely benign -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.038	T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.51	T;T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.11	T;T;T
Vest4		0.57
MVP		0.21
ClinPred		0.036	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199573929; hg19: chr2-73675690; COSMIC: COSV52512248; COSMIC: COSV52512248;