rs6724782

chr2-73452863-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378454.1(ALMS1):c.6336T>A(p.Ser2112Arg) 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 1,613,406 control chromosomes in the GnomAD database, including 66,846 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S2112S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (15917 hom., cov: 32)
  • Exomes 𝑓: 0.24 (50929 hom.)
• Consequence: ALMS1 NM_001378454.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0800

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.135518E-7).
• BP6: Variant 2-73452863-T-A is Benign according to our data. Variant chr2-73452863-T-A is described in ClinVar as [Benign]. Clinvar id is 383759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.6336T>A	p.Ser2112Arg	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.6339T>A	p.Ser2113Arg	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.6336T>A	p.Ser2112Arg	missense_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58803 AN: 151986 Hom.: 15854 Cov.: 32

Gnomad AFR AF: 0.768

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.00714

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.340

GnomAD3 exomes AF: 0.267 AC: 66163 AN: 248136 Hom.: 12180 AF XY: 0.249 AC XY: 33540 AN XY: 134740

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.00608

Gnomad SAS exome AF: 0.160

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.244

GnomAD4 exome AF: 0.244 AC: 356982 AN: 1461302 Hom.: 50929 Cov.: 38 AF XY: 0.240 AC XY: 174574 AN XY: 726966

Gnomad4 AFR exome AF: 0.781

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.0122

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.237

Gnomad4 OTH exome AF: 0.251

GnomAD4 genome AF: 0.387 AC: 58929 AN: 152104 Hom.: 15917 Cov.: 32 AF XY: 0.380 AC XY: 28281 AN XY: 74336

Gnomad4 AFR AF: 0.768

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.00716

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.336

Alfa AF: 0.274 Hom.: 2353

Bravo AF: 0.416

TwinsUK AF: 0.229 AC: 850

ALSPAC AF: 0.234 AC: 901

ESP6500AA AF: 0.740 AC: 2748

ESP6500EA AF: 0.239 AC: 1956

ExAC AF: 0.269 AC: 32471

Asia WGS AF: 0.124 AC: 431 AN: 3478

EpiCase AF: 0.233

EpiControl AF: 0.237

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ser2111Arg in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.75% (1160/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6724782). -
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	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. -

Alstrom syndrome Benign:3

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

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	0.046
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.12
Dann	Benign	0.66
DEOGEN2	Benign	0.0074	T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.11	T;T;T
MetaRNN	Benign	9.1e-7	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
Sift4G	Benign	0.63	T;T;T
Vest4		0.037
ClinPred		0.0043	T
GERP RS		-5.1
Varity_R		0.026
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

Other links and lift over

dbSNP: rs6724782; hg19: chr2-73679990; COSMIC: COSV52517254; COSMIC: COSV52517254;