rs75434052

Positions:

• chr2-73451696-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001378454.1(ALMS1):​c.5169A>G​(p.Gln1723=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,613,198 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (86 hom.)
• Consequence: ALMS1 NM_001378454.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.78

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=-0.86).
• BP6: Variant 2-73451696-A-G is Benign according to our data. Variant chr2-73451696-A-G is described in ClinVar as [Benign]. Clinvar id is 221016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1	c.5169A>G	p.Gln1723=	synonymous_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4	c.5172A>G	p.Gln1724=	synonymous_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6	c.5169A>G	p.Gln1723=	synonymous_variant	8/23	1	NM_001378454.1	P3

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2475 AN: 151256 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00618

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0134

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00863

GnomAD3 exomes AF: 0.00411 AC: 1023 AN: 248984 Hom.: 25 AF XY: 0.00325 AC XY: 439 AN XY: 135068

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.00264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00179 AC: 2617 AN: 1461820 Hom.: 86 Cov.: 39 AF XY: 0.00161 AC XY: 1171 AN XY: 727220

Gnomad4 AFR exome AF: 0.0616

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0164 AC: 2480 AN: 151378 Hom.: 68 Cov.: 32 AF XY: 0.0154 AC XY: 1139 AN XY: 74014

Gnomad4 AFR AF: 0.0570

Gnomad4 AMR AF: 0.00618

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000236

Gnomad4 OTH AF: 0.00853

Alfa AF: 0.00719 Hom.: 13

Bravo AF: 0.0182

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gln1722Gln in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 5.86% (573/9782) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs75434052). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 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	-0.86
CADD	Benign	0.0090
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs75434052; hg19: chr2-73678823;