rs62151609

chr2-73451990-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001378454.1(ALMS1):c.5463G>A(p.Pro1821=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00792 in 1,612,522 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (71 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.873

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-73451990-G-A is Benign according to our data. Variant chr2-73451990-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.873 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00877 (1322/150752) while in subpopulation NFE AF= 0.00966 (653/67630). AF 95% confidence interval is 0.00904. There are 8 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.5463G>A	p.Pro1821=	synonymous_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5466G>A	p.Pro1822=	synonymous_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5463G>A	p.Pro1821=	synonymous_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.00877 AC: 1321 AN: 150630 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00638

Gnomad AMI AF: 0.0188

Gnomad AMR AF: 0.00310

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.00964

Gnomad OTH AF: 0.00435

GnomAD3 exomes AF: 0.00725 AC: 1804 AN: 248922 Hom.: 19 AF XY: 0.00708 AC XY: 957 AN XY: 135136

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.00844

Gnomad OTH exome AF: 0.00661

GnomAD4 exome AF: 0.00783 AC: 11452 AN: 1461770 Hom.: 71 Cov.: 38 AF XY: 0.00775 AC XY: 5634 AN XY: 727200

Gnomad4 AFR exome AF: 0.00702

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.0274

Gnomad4 NFE exome AF: 0.00812

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00877 AC: 1322 AN: 150752 Hom.: 8 Cov.: 32 AF XY: 0.00977 AC XY: 720 AN XY: 73664

Gnomad4 AFR AF: 0.00639

Gnomad4 AMR AF: 0.00310

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.00966

Gnomad4 OTH AF: 0.00430

Alfa AF: 0.00862 Hom.: 1

Bravo AF: 0.00687

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00676

EpiControl AF: 0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro1820Pro in exon 8 of ALMS1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 2.93% (194/6614) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs62151609). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 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. -

Alstrom syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 02, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ALMS1: BP4, BP7, BS2 -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 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
BayesDel_noAF	Benign	-0.90
Cadd	Benign	5.7
Dann	Benign	0.65

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: rs62151609; hg19: chr2-73679117; COSMIC: COSV52508012; COSMIC: COSV52508012;