chr2-73599437-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001378454.1(ALMS1):c.11584T>C(p.Ser3862Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000979 in 1,613,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 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 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.31

Variant links:

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]

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.049546123).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000525 (80/152334) while in subpopulation AFR AF= 0.00185 (77/41580). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.11584T>C	p.Ser3862Pro	missense_variant	Exon 17 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.11584T>C	p.Ser3862Pro	missense_variant	Exon 17 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.11584T>C	p.Ser3862Pro	missense_variant	Exon 17 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249020

Hom.:

AF XY:

0.0000814

AC XY:

AN XY:

135098

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1461192

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.00209

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000525

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000187

Hom.:

Bravo

AF:

0.000525

ESP6500AA

AF:

0.00163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 17, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ser3863Pro variant in ALMS1 has not been previously reported in individual s with hearing loss or Alstrom syndrome but has been identified in 0.18% (44/240 14) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 406025). Computational prediction tools and conservation analysis do not prov ide strong support for or against an impact to the protein. In summary, the clin ical significance of the p.Ser3863Pro variant is uncertain. ACMG/AMP Criteria ap plied: BS1_Supporting. -

Jan 17, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALMS1 c.11581T>C (p.Ser3861Pro, also known as c.11587T>C/p.S3863P in RefSeq) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249020 control chromosomes, predominantly at a frequency of 0.0018 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.0018 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.11581T>C in individuals affected with Cardiomyopathy or Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with a pathogenic variant has been reported within our laboratory (TTR: c.424G_A, p.Val142Ile), providing supporting evidence for a benign role. Three ClinVar submitters have assessed this variant since 2014: all laboratories classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as of VUS-possibly benign. -

Alstrom syndrome

Uncertain:2

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3863 of the ALMS1 protein (p.Ser3863Pro). This variant is present in population databases (rs202227966, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423980). 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. -

Mar 04, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Uncertain:1

Oct 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Cardiovascular phenotype

Benign:1

Dec 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.33

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.2

PrimateAI

Benign

0.36

Sift4G

Uncertain

0.018

D;D

Vest4

0.51

MVP

0.71

ClinPred

0.11

GERP RS

3.8

Varity_R

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over