2-73448717-C-T

Position:

chr2-73448717-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001378454.1(ALMS1):c.2190C>T(p.Phe730Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 1,613,450 control chromosomes in the GnomAD database, including 307,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 22487 hom., cov: 31)

Exomes 𝑓: 0.62 ( 284857 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -1.01

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 2-73448717-C-T is Benign according to our data. Variant chr2-73448717-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 383768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 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.2190C>T	p.Phe730Phe	synonymous_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.2190C>T	p.Phe730Phe	synonymous_variant	8/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.2190C>T	p.Phe730Phe	synonymous_variant	8/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.508

AC:

77090

AN:

151616

Hom.:

22494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.690

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.620

Gnomad EAS

AF:

0.766

Gnomad SAS

AF:

0.672

Gnomad FIN

AF:

0.609

Gnomad MID

AF:

0.653

Gnomad NFE

AF:

0.629

Gnomad OTH

AF:

0.549

GnomAD3 exomes

AF:

0.603

AC:

150038

AN:

248858

Hom.:

47079

AF XY:

0.614

AC XY:

82897

AN XY:

134986

show subpopulations

Gnomad AFR exome

AF:

0.180

Gnomad AMR exome

AF:

0.545

Gnomad ASJ exome

AF:

0.627

Gnomad EAS exome

AF:

0.777

Gnomad SAS exome

AF:

0.668

Gnomad FIN exome

AF:

0.610

Gnomad NFE exome

AF:

0.629

Gnomad OTH exome

AF:

0.624

GnomAD4 exome

AF:

0.619

AC:

905426

AN:

1461718

Hom.:

284857

Cov.:

AF XY:

0.622

AC XY:

451994

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.177

Gnomad4 AMR exome

AF:

0.543

Gnomad4 ASJ exome

AF:

0.628

Gnomad4 EAS exome

AF:

0.747

Gnomad4 SAS exome

AF:

0.661

Gnomad4 FIN exome

AF:

0.615

Gnomad4 NFE exome

AF:

0.628

Gnomad4 OTH exome

AF:

0.620

GnomAD4 genome

AF:

0.508

AC:

77085

AN:

151732

Hom.:

22487

Cov.:

AF XY:

0.514

AC XY:

38113

AN XY:

74158

show subpopulations

Gnomad4 AFR

AF:

0.197

Gnomad4 AMR

AF:

0.559

Gnomad4 ASJ

AF:

0.620

Gnomad4 EAS

AF:

0.767

Gnomad4 SAS

AF:

0.672

Gnomad4 FIN

AF:

0.609

Gnomad4 NFE

AF:

0.629

Gnomad4 OTH

AF:

0.549

Alfa

AF:

0.593

Hom.:

35457

Bravo

AF:

0.488

Asia WGS

AF:

0.694

AC:

2414

AN:

3478

EpiCase

AF:

0.637

EpiControl

AF:

0.632

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Phe729Phe in exon 8 of ALMS1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 77.44% (6674/8618) o f East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs7598901). -
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:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
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	- -

ALMS1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 10, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.78

CADD

Benign

2.4

DANN

Benign

0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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