2-73557350-T-A

Position:

chr2-73557350-T-A

Variant summary

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

The NM_001378454.1(ALMS1):c.10209T>A(p.Thr3403Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,614,092 control chromosomes in the GnomAD database, including 906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 124 hom., cov: 32)

Exomes 𝑓: 0.013 ( 782 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.44

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:

ALMS1 (HGNC:):

ALMS1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 2-73557350-T-A is Benign according to our data. Variant chr2-73557350-T-A is described in ClinVar as [Benign]. Clinvar id is 389388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.44 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0834 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.10209T>A	p.Thr3403Thr	synonymous_variant	14/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.10209T>A	p.Thr3403Thr	synonymous_variant	14/23		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.10209T>A	p.Thr3403Thr	synonymous_variant	14/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3333

AN:

152174

Hom.:

120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0868

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.0320

AC:

7963

AN:

249118

Hom.:

620

AF XY:

0.0249

AC XY:

3370

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.00189

Gnomad SAS exome

AF:

0.00297

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.00616

Gnomad OTH exome

AF:

0.0242

GnomAD4 exome

AF:

0.0125

AC:

18343

AN:

1461800

Hom.:

782

Cov.:

AF XY:

0.0116

AC XY:

8422

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0302

Gnomad4 AMR exome

AF:

0.165

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.00804

Gnomad4 SAS exome

AF:

0.00315

Gnomad4 FIN exome

AF:

0.0182

Gnomad4 NFE exome

AF:

0.00681

Gnomad4 OTH exome

AF:

0.0116

GnomAD4 genome

AF:

0.0220

AC:

3348

AN:

152292

Hom.:

124

Cov.:

AF XY:

0.0234

AC XY:

1742

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.0308

Gnomad4 AMR

AF:

0.0873

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00270

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.00625

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.00515

Hom.:

Bravo

AF:

0.0294

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00545

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Thr3402Thr in exon 14 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 19.40% (2239/11544 ) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs34617744). -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 10, 2018	- -

Alstrom syndrome

Benign:2

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	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 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

-0.73

CADD

Benign

6.4

DANN

Benign

0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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