2-73450771-G-C

Variant names:

Variant summary

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

The NM_001378454.1(ALMS1):c.4244G>C(p.Gly1415Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,607,392 control chromosomes in the GnomAD database, including 66,432 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 15837 hom., cov: 31)

Exomes 𝑓: 0.24 ( 50595 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.83

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.505922E-7).

BP6

Variant 2-73450771-G-C is Benign according to our data. Variant chr2-73450771-G-C is described in ClinVar as [Benign]. Clinvar id is 379229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.4244G>C	p.Gly1415Ala	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.4244G>C	p.Gly1415Ala	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.4244G>C	p.Gly1415Ala	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

58505

AN:

146478

Hom.:

15774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.773

Gnomad AMI

AF:

0.286

Gnomad AMR

AF:

0.385

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00808

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.350

GnomAD3 exomes

AF:

0.268

AC:

66158

AN:

247308

Hom.:

12193

AF XY:

0.250

AC XY:

33493

AN XY:

134160

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.00620

Gnomad SAS exome

AF:

0.163

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.246

GnomAD4 exome

AF:

0.243

AC:

355637

AN:

1460804

Hom.:

50595

Cov.:

AF XY:

0.239

AC XY:

173873

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.781

Gnomad4 AMR exome

AF:

0.409

Gnomad4 ASJ exome

AF:

0.169

Gnomad4 EAS exome

AF:

0.0123

Gnomad4 SAS exome

AF:

0.167

Gnomad4 FIN exome

AF:

0.232

Gnomad4 NFE exome

AF:

0.237

Gnomad4 OTH exome

AF:

0.249

GnomAD4 genome

AF:

0.400

AC:

58633

AN:

146588

Hom.:

15837

Cov.:

AF XY:

0.394

AC XY:

28146

AN XY:

71466

show subpopulations

Gnomad4 AFR

AF:

0.773

Gnomad4 AMR

AF:

0.385

Gnomad4 ASJ

AF:

0.181

Gnomad4 EAS

AF:

0.00810

Gnomad4 SAS

AF:

0.164

Gnomad4 FIN

AF:

0.262

Gnomad4 NFE

AF:

0.248

Gnomad4 OTH

AF:

0.348

Alfa

AF:

0.220

Hom.:

3098

Bravo

AF:

0.415

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.233

AC:

898

ESP6500AA

AF:

0.738

AC:

2767

ESP6500EA

AF:

0.238

AC:

1956

ExAC

AF:

0.268

AC:

32390

Asia WGS

AF:

0.126

AC:

438

AN:

3478

EpiCase

AF:

0.233

EpiControl

AF:

0.238

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly1414Ala in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.82% (1161/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6546837). -

Sep 22, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alstrom syndrome

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.051

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0020

DANN

Benign

0.10

DEOGEN2

Benign

0.0059

T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00028

LIST_S2

Benign

0.086

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.23

Sift4G

Benign

0.80

T;T;T

Vest4

0.020

ClinPred

0.0067

GERP RS

-0.18

Varity_R

0.028

gMVP

0.017

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