rs201154998

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001378454.1(ALMS1):c.2536G>A(p.Gly846Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.503

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=0.011483073).

BP6

Variant 2-73449063-G-A is Benign according to our data. Variant chr2-73449063-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391955.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.2536G>A	p.Gly846Arg	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.2539G>A	p.Gly847Arg	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.2536G>A	p.Gly846Arg	missense_variant	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000701

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000723

AC:

AN:

248836

Hom.:

AF XY:

0.0000519

AC XY:

AN XY:

134962

show subpopulations

Gnomad AFR exome

AF:

0.000904

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000204

AC:

AN:

152120

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000699

Gnomad4 AMR

AF:

0.000131

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

Alfa

AF:

0.0000738

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.000791

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000910

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 27, 2022

Variant summary: ALMS1 c.2533G>A/p.Gly845Arg (also known as c.2539G>A/p.G847R in RefSeq) results in a non-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 7.2e-05 in 248836 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (7.2e-05 vs 0.0022), allowing no conclusion about variant significance. c.2533G>A has been reported in the literature in individuals affected with congenital heart disease or inherited retinal and optical nerve disorders. These reports 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=2, likely benign n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2023

Identified in cohort of patients with syndromic or non-syndromic inherited retinal dystrophies (IRDs) (Dineiro et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32483926) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2019

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. -

Alstrom syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.36

Cadd

Benign

9.2

Dann

Benign

0.23

DEOGEN2

Benign

0.011

T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.16

T;T;T

M_CAP

Benign

0.0031

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.93

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.18

Sift4G

Benign

0.15

T;T;T

Vest4

0.14

MVP

0.13

ClinPred

0.0030

GERP RS

-0.77

Varity_R

0.039

gMVP

0.040

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