rs3820700

Positions:

Variant summary

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

The NM_001378454.1(ALMS1):c.7724G>A(p.Ser2575Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,613,854 control chromosomes in the GnomAD database, including 16,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1271 hom., cov: 32)

Exomes 𝑓: 0.14 ( 14863 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.36

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=0.0017927587).

BP6

Variant 2-73489683-G-A is Benign according to our data. Variant chr2-73489683-G-A is described in ClinVar as [Benign]. Clinvar id is 383774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.21 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.7724G>A	p.Ser2575Asn	missense_variant	10/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.7724G>A	p.Ser2575Asn	missense_variant	10/23		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.7724G>A	p.Ser2575Asn	missense_variant	10/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

18957

AN:

151956

Hom.:

1272

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0808

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.117

GnomAD3 exomes

AF:

0.134

AC:

33514

AN:

249504

Hom.:

2502

AF XY:

0.139

AC XY:

18878

AN XY:

135370

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.0523

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.214

Gnomad SAS exome

AF:

0.169

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.134

GnomAD4 exome

AF:

0.139

AC:

203585

AN:

1461778

Hom.:

14863

Cov.:

AF XY:

0.141

AC XY:

102416

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.0546

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.240

Gnomad4 SAS exome

AF:

0.169

Gnomad4 FIN exome

AF:

0.154

Gnomad4 NFE exome

AF:

0.137

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.125

AC:

18961

AN:

152076

Hom.:

1271

Cov.:

AF XY:

0.125

AC XY:

9296

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.0807

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.221

Gnomad4 SAS

AF:

0.175

Gnomad4 FIN

AF:

0.149

Gnomad4 NFE

AF:

0.135

Gnomad4 OTH

AF:

0.122

Alfa

AF:

0.132

Hom.:

3375

Bravo

AF:

0.118

TwinsUK

AF:

0.144

AC:

535

ALSPAC

AF:

0.141

AC:

542

ESP6500AA

AF:

0.0982

AC:

376

ESP6500EA

AF:

0.130

AC:

1073

ExAC

AF:

0.138

AC:

16617

Asia WGS

AF:

0.182

AC:

631

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.133

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:3

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

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ser2574Asn in exon 10 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 21.64% (1866/8622) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs3820700). -

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

0.28

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.033

T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.45

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.21

ClinPred

0.013

GERP RS

4.5

Varity_R

0.097

gMVP

0.082

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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