2-73599494-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001378454.1(ALMS1):c.11641C>T(p.His3881Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,580 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3881D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:10
• Conservation: PhyloP100: 2.02

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01774621).
• BP6: Variant 2-73599494-C-T is Benign according to our data. Variant chr2-73599494-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240979.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (157/152274) while in subpopulation NFE AF= 0.00181 (123/68018). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.11641C>T	p.His3881Tyr	missense_variant	17/23	ENST00000613296.6
ALMS1	NM_015120.4	c.11644C>T	p.His3882Tyr	missense_variant	17/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.11641C>T	p.His3881Tyr	missense_variant	17/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000964 AC: 240 AN: 248972 Hom.: 0 AF XY: 0.00103 AC XY: 139 AN XY: 135070

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000280

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00172 AC: 2512 AN: 1461306 Hom.: 2 Cov.: 31 AF XY: 0.00169 AC XY: 1232 AN XY: 726972

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.00211

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74450

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000926

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000271 AC: 1

ESP6500EA AF: 0.00244 AC: 20

ExAC AF: 0.00104 AC: 126

EpiCase AF: 0.00202

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 04, 2018	The p.His3880Tyr variant is classifed as likely benign because it has been ident ified in 0.17% (218/126250) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org), and computational prediction tools and conservation analysis s uggest that this variant may not impact the protein. Furthermore, although this variant has been reported in two individuals with features of Alstrom syndrome, both individuals harbored pathogenic variants in BBS1 and BBS2 indicating a diag nosis of Bardet-Biedl syndrome (Joy 2007, Chen 2017, Alvarez-Satta 2017). In vi tro functional studies performed in patient fibroblast cells indicate that the v ariant did not have an effect on the protein function (Chen 2017, Alvarez-Satta 2017). This variant is reported in ClinVar (Variation ID: 240979). In summary, t his variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP5, BS3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2022	Variant summary: ALMS1 c.11638C>T (p.His3880Tyr, also known as c.11644C>T in RefSeq) 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 0.00097 in 280780 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.11638C>T has been reported in the literature in individuals affected with Alstrom Syndrome and Bardet-Biedl syndrome (Joy_2007, Pereiro_2010, Ozanturk_2015, Castro-Sanchez_2015, Chen_2017). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported, one individual harbored BBS1 c.1169T>G (p.Met390Arg, homozygote, Castro-Sanchez_2015) and one individual carried BBS2 c.613-1G>C and BBS2 c.717+1G>A (Chen_2017), providing supporting evidence for a benign role. Functional studies report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Alvarez-Satta_2017, Chen_2017). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ALMS1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	This variant is associated with the following publications: (PMID: 18154657, 25846608, 28502102, 26082521, 28717663) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Alstrom syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2022	This sequence change replaces histidine with tyrosine at codon 3882 of the ALMS1 protein (p.His3882Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs142278066, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with an ALMS1-related disease. However, in one of these individuals the variant was found to co-occur with 2 pathogenic variants in the BBS2 gene. (PMID: 18154657, 28502102). ClinVar contains an entry for this variant (Variation ID: 240979). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Monogenic diabetes Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 15, 2019

ACMG criteria: BP4 (REVEL 0.042 + 5 predictors), BP1 (missense in gene where truncating variants are mechanism of disease), PM3 (PMID:18154657 reported a compound het AS patient also carrying V424I) = likely benign -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2021

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	0.094
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
Sift4G	Uncertain	0.013	D;D
Vest4		0.28
MVP		0.23
ClinPred		0.0060	T
GERP RS		3.9
Varity_R		0.065
gMVP		0.097

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: rs142278066; hg19: chr2-73826621;