2-73453164-G-T

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.6637G>T(p.Asp2213Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.12

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=0.040798575).

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000198 (29/1461746) while in subpopulation AFR AF= 0.000777 (26/33474). AF 95% confidence interval is 0.000544. There are 0 homozygotes in gnomad4_exome. There are 11 alleles in male gnomad4_exome subpopulation. Median coverage is 37. 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.6637G>T	p.Asp2213Tyr	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.6637G>T	p.Asp2213Tyr	missense_variant	Exon 8 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.6637G>T	p.Asp2213Tyr	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

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:

0.00

GnomAD3 exomes

AF:

0.0000482

AC:

AN:

248802

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134994

show subpopulations

Gnomad AFR exome

AF:

0.000775

Gnomad AMR exome

AF:

0.00

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:

0.0000198

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000652

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:

0.00

Bravo

AF:

0.000193

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:4

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2214 of the ALMS1 protein (p.Asp2214Tyr). This variant is present in population databases (rs367656336, gnomAD 0.07%). 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: 459879). 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. -

Jul 12, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Apr 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Cardiovascular phenotype

Benign:1

Mar 24, 2023

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

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.041

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.24

Sift4G

Uncertain

0.044

D;D;D

Vest4

0.26

MVP

0.19

ClinPred

0.050

GERP RS

1.5

Varity_R

0.054

gMVP

0.16

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