rs17009061

Positions:

chr2-73452313-G-A

Variant summary

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

The NM_001378454.1(ALMS1):c.5786G>A(p.Arg1929Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,848 control chromosomes in the GnomAD database, including 920 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 0.022 ( 125 hom., cov: 32)

Exomes 𝑓: 0.013 ( 795 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.06

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=0.0014262199).

BP6

Variant 2-73452313-G-A is Benign according to our data. Variant chr2-73452313-G-A is described in ClinVar as [Benign]. Clinvar id is 389387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0836 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.5786G>A	p.Arg1929Gln	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.5789G>A	p.Arg1930Gln	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.5786G>A	p.Arg1929Gln	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0221

AC:

3359

AN:

151936

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0870

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00290

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00649

Gnomad OTH

AF:

0.0173

GnomAD3 exomes

AF:

0.0321

AC:

7996

AN:

249024

Hom.:

628

AF XY:

0.0250

AC XY:

3381

AN XY:

135092

show subpopulations

Gnomad AFR exome

AF:

0.0337

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00189

Gnomad SAS exome

AF:

0.00333

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.00633

Gnomad OTH exome

AF:

0.0247

GnomAD4 exome

AF:

0.0128

AC:

18754

AN:

1461794

Hom.:

795

Cov.:

AF XY:

0.0118

AC XY:

8616

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0301

Gnomad4 AMR exome

AF:

0.166

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.00806

Gnomad4 SAS exome

AF:

0.00361

Gnomad4 FIN exome

AF:

0.0184

Gnomad4 NFE exome

AF:

0.00710

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.0222

AC:

3374

AN:

152054

Hom.:

125

Cov.:

AF XY:

0.0236

AC XY:

1755

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0309

Gnomad4 AMR

AF:

0.0875

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00291

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.00649

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.00910

Hom.:

Bravo

AF:

0.0295

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00882

AC:

ESP6500AA

AF:

0.0292

AC:

110

ESP6500EA

AF:

0.00707

AC:

ExAC

AF:

0.0269

AC:

3251

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00551

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:3

Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs17009061 in Alstrom syndrome yet. -
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	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg1928Gln in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 19.32% (2222/11500) of Latino chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs17009061). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: BP4 (REVEL score 0.039 + 7 predictors), BS1 (17.7% MAF in gnomAD Latino, overall MAF 3%), BA1 (641 homozygotes in gnomAD), BP1 (missense in gene with truncating cause disease): Benign; likely in cis with the other ALMS1 variant -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 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

0.057

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.6

DANN

Benign

0.66

DEOGEN2

Benign

0.015

T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00026

LIST_S2

Benign

0.40

T;T;T

MetaRNN

Benign

0.0014

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

Sift4G

Benign

1.0

T;T;T

Vest4

0.12

ClinPred

0.0011

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.039

gMVP

0.019

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