2-73602245-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001378454.1(ALMS1):c.12175C>T(p.Leu4059Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,824 control chromosomes in the GnomAD database, including 62,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 13995 hom., cov: 32)

Exomes 𝑓: 0.24 ( 48469 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.33

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 2-73602245-C-T is Benign according to our data. Variant chr2-73602245-C-T is described in ClinVar as [Benign]. Clinvar id is 383765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55947

AN:

151940

Hom.:

13938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.00715

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.323

GnomAD3 exomes

AF:

0.260

AC:

65253

AN:

251166

Hom.:

11501

AF XY:

0.242

AC XY:

32914

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.722

Gnomad AMR exome

AF:

0.402

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.00566

Gnomad SAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.240

AC:

351385

AN:

1461766

Hom.:

48469

Cov.:

AF XY:

0.236

AC XY:

171876

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.715

Gnomad4 AMR exome

AF:

0.402

Gnomad4 ASJ exome

AF:

0.151

Gnomad4 EAS exome

AF:

0.0118

Gnomad4 SAS exome

AF:

0.166

Gnomad4 FIN exome

AF:

0.231

Gnomad4 NFE exome

AF:

0.236

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.369

AC:

56067

AN:

152058

Hom.:

13995

Cov.:

AF XY:

0.363

AC XY:

26980

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.710

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.158

Gnomad4 EAS

AF:

0.00716

Gnomad4 SAS

AF:

0.149

Gnomad4 FIN

AF:

0.243

Gnomad4 NFE

AF:

0.238

Gnomad4 OTH

AF:

0.319

Alfa

AF:

0.299

Hom.:

4756

Bravo

AF:

0.394

Asia WGS

AF:

0.118

AC:

409

AN:

3478

EpiCase

AF:

0.230

EpiControl

AF:

0.235

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu4058Leu in exon 20 of ALMS1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 80.11% (1059/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs1052162). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 09, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alstrom syndrome

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.27

CADD

Benign

7.1

DANN

Benign

0.91

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