2-73424839-C-T

Position:

chr2-73424839-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.1174C>T(p.Arg392Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,606,736 control chromosomes in the GnomAD database, including 66,086 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 Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 15844 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50242 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0890

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.4957634E-7).

BP6

Variant 2-73424839-C-T is Benign according to our data. Variant chr2-73424839-C-T is described in ClinVar as [Benign]. Clinvar id is 383753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.1174C>T	p.Arg392Cys	missense_variant	5/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.1174C>T	p.Arg392Cys	missense_variant	5/23		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.1174C>T	p.Arg392Cys	missense_variant	5/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58555

AN:

151916

Hom.:

15781

Cov.:

show subpopulations

Gnomad AFR

AF:

0.767

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.338

GnomAD3 exomes

AF:

0.266

AC:

65285

AN:

245640

Hom.:

12050

AF XY:

0.248

AC XY:

33031

AN XY:

133114

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.00614

Gnomad SAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.243

AC:

353524

AN:

1454702

Hom.:

50242

Cov.:

AF XY:

0.239

AC XY:

172639

AN XY:

722594

show subpopulations

Gnomad4 AFR exome

AF:

0.780

Gnomad4 AMR exome

AF:

0.407

Gnomad4 ASJ exome

AF:

0.171

Gnomad4 EAS exome

AF:

0.0123

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.231

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.248

GnomAD4 genome

AF:

0.386

AC:

58681

AN:

152034

Hom.:

15844

Cov.:

AF XY:

0.379

AC XY:

28175

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.767

Gnomad4 AMR

AF:

0.373

Gnomad4 ASJ

AF:

0.175

Gnomad4 EAS

AF:

0.00715

Gnomad4 SAS

AF:

0.150

Gnomad4 FIN

AF:

0.243

Gnomad4 NFE

AF:

0.239

Gnomad4 OTH

AF:

0.334

Alfa

AF:

0.252

Hom.:

14238

Bravo

AF:

0.414

TwinsUK

AF:

0.229

AC:

848

ALSPAC

AF:

0.233

AC:

897

ESP6500AA

AF:

0.737

AC:

2778

ESP6500EA

AF:

0.237

AC:

1953

ExAC

AF:

0.268

AC:

32310

Asia WGS

AF:

0.123

AC:

430

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg392Cys in exon 5 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 87.82% (1161/1322) of African chrom osomes by the 1000 Genomes Project (Phase 3; dbSNP rs3813227). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Alstrom syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2018

This alteration is classified as 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

0.061

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.2

DANN

Benign

0.36

DEOGEN2

Benign

0.0060

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.32

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

.;N;.

PrimateAI

Benign

0.24

Sift4G

Benign

0.57

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.064

ClinPred

0.00046

GERP RS

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.021

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