2-73451886-A-G

Position:

chr2-73451886-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.5359A>G(p.Asn1787Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,611,588 control chromosomes in the GnomAD database, including 259 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1787I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 27 hom., cov: 32)

Exomes 𝑓: 0.015 ( 232 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.59

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=0.002682358).

BP6

Variant 2-73451886-A-G is Benign according to our data. Variant chr2-73451886-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 220971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-73451886-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0145 (2173/149794) while in subpopulation SAS AF= 0.0191 (89/4668). AF 95% confidence interval is 0.0172. There are 27 homozygotes in gnomad4. There are 1136 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.5359A>G	p.Asn1787Asp	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.5362A>G	p.Asn1788Asp	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.5359A>G	p.Asn1787Asp	missense_variant	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2173

AN:

149672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00283

Gnomad AMI

AF:

0.0410

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000203

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0175

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0117

GnomAD3 exomes

AF:

0.0147

AC:

3665

AN:

248994

Hom.:

AF XY:

0.0157

AC XY:

2121

AN XY:

135076

show subpopulations

Gnomad AFR exome

AF:

0.00247

Gnomad AMR exome

AF:

0.00675

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.0159

Gnomad FIN exome

AF:

0.0339

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0155

AC:

22642

AN:

1461794

Hom.:

232

Cov.:

AF XY:

0.0158

AC XY:

11486

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00251

Gnomad4 AMR exome

AF:

0.00693

Gnomad4 ASJ exome

AF:

0.0181

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.0352

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0145

AC:

2173

AN:

149794

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1136

AN XY:

73250

show subpopulations

Gnomad4 AFR

AF:

0.00282

Gnomad4 AMR

AF:

0.0147

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000204

Gnomad4 SAS

AF:

0.0191

Gnomad4 FIN

AF:

0.0386

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.0116

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0113

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00243

AC:

ESP6500EA

AF:

0.0163

AC:

134

ExAC

AF:

0.0144

AC:

1738

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0183

EpiControl

AF:

0.0175

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2017	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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asn1786Asp in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 3.54% (234/6614) of Finnish chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs45608038). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Alstrom syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 29, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALMS1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Oct 26, 2018

ACMG criteria: BP4 (REVEL =0.006 + 9 predictors), BA1 (1.5% MAF in gnomAD, 3.5 % in gnomAD European Finnish population), BS2 (60 homozygotes in gnomAD)= benign -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

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

0.075

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0010

DANN

Benign

0.33

DEOGEN2

Benign

0.011

T;.;.

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.7

FATHMM_MKL

Benign

0.0051

LIST_S2

Benign

0.0027

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

Sift4G

Benign

0.32

T;T;T

Vest4

0.044

ClinPred

0.0011

GERP RS

-9.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.028

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