2-73447980-A-G

Position:

• chr2-73447980-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.1453A>G​(p.Ile485Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,612,516 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (5 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: 0.408

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=0.004206747).
• BP6: Variant 2-73447980-A-G is Benign according to our data. Variant chr2-73447980-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198873.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=4}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00185 (282/152282) while in subpopulation AMR AF= 0.00491 (75/15286). AF 95% confidence interval is 0.00401. There are 0 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1	c.1453A>G	p.Ile485Val	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4	c.1453A>G	p.Ile485Val	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6	c.1453A>G	p.Ile485Val	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00172 AC: 428 AN: 248254 Hom.: 1 AF XY: 0.00174 AC XY: 234 AN XY: 134660

Gnomad AFR exome AF: 0.000711

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00172 AC: 2508 AN: 1460234 Hom.: 5 Cov.: 32 AF XY: 0.00168 AC XY: 1219 AN XY: 726426

Gnomad4 AFR exome AF: 0.000449

Gnomad4 AMR exome AF: 0.00314

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00195

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74480

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00491

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00222 Hom.: 3

Bravo AF: 0.00219

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000535 AC: 2

ESP6500EA AF: 0.00232 AC: 19

ExAC AF: 0.00160 AC: 193

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00197

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ALMS1: BP4, BS2 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	May 02, 2017	Given this variant's presence in a large number of controls, no case data, the fact that Valine is the default amino acid in more than one species, and the autosomal recessive inheritance pattern of the disease with which ALMS1 is associated, we consider this variant a variant of uncertain significance, probably benign, and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There is no case data for this variant (and searched alternative notations p.Ile485Val) 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. Most Pathogenic variants in ALMS1 listed in ClinVar are truncating (frameshift or nonsense) and not missense like this one. According to ExAC, ALMS1 is tolerant of both synonymous (z= -2.46) and missense (z= -6.40) change, while it is intolerant to loss-of-function change (pLI= 0.00). This observation agrees with available case data: published cases of Alström syndrome are caused by a loss-of-function of both copies of the ALMS1 gene. This is a conservative amino acid change, resulting in the replacement of a nonpolar Isoleucine with a nonpolar Valine. Isoleucine at this location is poorly conserved across mammalian species. In fact, Valine is the default amino acid in at least two mammalian species, suggesting that this missense change does not adversely affect protein function. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). There are no Likely Pathogenic or Pathogenic variants listed within 10 amino acids of this residue in ClinVar as of 4/29/2017. This variant is present in ClinVar. It has been submitted by Emory Genetics Laboratory and Invitae. Both labs classify this variant as a variant of uncertain significance. The testing lab uses a different Ensembl transcript for this gene than that which directly corresponds to the HGVS transcript (ENST00000264448) according to publicly-available software. According to the ENST00000264448 transcript, this variant would be reported as p.Ile486Val. This variant (rs73945001) was reported in 456 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. (Because gnomAD uses a different transcript, it is listed as p.Ile485Val.) The overall MAF is 0.165%. In Latinos the MAF 0.25%, and in non-Finnish Europeans it is 0.23%. Our patient’s ancestry is from Portugal and Germany. The phenotype of the individuals in gnomAD is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -

Alstrom syndrome Uncertain:1 Benign:3

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 rs73945001 in Alstrom syndrome yet. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2020	Variant summary: ALMS1 c.1453A>G (p.Ile485Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 279644 control chromosomes in the gnomAD database, including 2 homozygotes. The variant was found predominantly within the Latino- (allele frequency: 0.0026) and the non-Finnish European (0.0023) subpopulations, and the observed variant frequency within these control individuals is approximately 1.3 to 1.4-fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome with Dilated Cardiomyopathy phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism. To our knowledge, no occurrence of c.1453A>G in individuals affected with Alstrom Syndrome with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x), likely benign (1x) or benign (2x). Based on the evidence outlined above, the variant was classified as benign. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 08, 2019

ACMG criteria: BP4 (8 predictors, REVEL 0.017), BP1(missense variant when mutations are truncating), BS2 (2 homozygotes in gnomAD Eur NF), BS1 (0.2% MAF in gnomAD latino, eurNF, other)=benign (Emory classified as VUS) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 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	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.43
DEOGEN2	Benign	0.020	T;T;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	.;L;.
PrimateAI	Benign	0.24	T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.10	.;B;.
Vest4		0.051
MVP		0.17
ClinPred		0.0031	T
GERP RS		1.4
Varity_R		0.025
gMVP		0.019

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: rs73945001; hg19: chr2-73675110;