rs201673771

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001378454.1(ALMS1):c.11708G>A(p.Arg3903Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000827 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 1 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.13

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:

ALMS1 (HGNC:):

ALMS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05411434).

BP6

Variant 2-73600717-G-A is Benign according to our data. Variant chr2-73600717-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387921.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000571 (87/152232) while in subpopulation NFE AF= 0.00107 (73/68028). AF 95% confidence interval is 0.000875. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.11708G>A	p.Arg3903Gln	missense_variant	18/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.11708G>A	p.Arg3903Gln	missense_variant	18/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.11708G>A	p.Arg3903Gln	missense_variant	18/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000504

AC:

126

AN:

250142

Hom.:

AF XY:

0.000464

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0000645

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000909

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000854

AC:

1248

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000826

AC XY:

601

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00107

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000571

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000900

Hom.:

Bravo

AF:

0.000563

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00164

AC:

ExAC

AF:

0.000462

AC:

EpiCase

AF:

0.000981

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2018	The p.Arg3904Gln variant in ALMS1 is classified as likely benign due to a lack o f conservation across species, including mammals. Of note, golden hamster, mouse and rat have a glutamine (Gln) at this position. It has been identified in 119/ 126668 European chromosomes by the Genome Aggregation Database (gnomAD, http://g nomad.broadinstitute.org, dbSNP rs201673771). ACMG/AMP Criteria applied: BP4_Str ong, BS1_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 24, 2023	Variant summary: ALMS1 c.11705G>A (p.Arg3902Gln) 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 0.0005 in 250142 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (0.0005 vs 0.0018), allowing no conclusion about variant significance. c.11705G>A has been reported in the literature in individuals affected/suspicion for Alstrom Syndrome (Marshall_2015) or Dilated Cardiomyopathy (Khan_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32483926, 34935411, 25846608). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Alstrom syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3904 of the ALMS1 protein (p.Arg3904Gln). This variant is present in population databases (rs201673771, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 387921). 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	The ALMS1 c.11708G>A; p.Arg3903Gln variant (rs201673771), also known as NM_015120.4: c.11711G>A; p.Arg3904Gln, has been reported in the literature as a variant of uncertain significance, but clinical information was not provided (Dineiro 2020). This variant is also reported in ClinVar (Variation ID: 387921). It is found in the general population with an overall allele frequency of 0.05% (146/281546 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is tolerated (REVEL: 0.092). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Dineiro M et al. Comprehensive genomic diagnosis of inherited retinal and optical nerve disorders reveals hidden syndromes and personalized therapeutic options. Acta Ophthalmol. 2020 Dec;98(8):e1034-e1048. PMID: 32483926. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 29, 2024

Reported in a cohort with a clinical diagnosis of blindness, no additional clinical or segregation information was provided (PMID: 32483926); In silico analysis indicates 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

Feb 14, 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

-0.35

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

T;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;T

M_CAP

Benign

0.0013

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.27

Sift4G

Benign

0.18

T;T

Vest4

0.45

MVP

0.37

ClinPred

0.075

GERP RS

3.5

Varity_R

0.034

gMVP

0.29

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