chr2-73450681-C-G

Position:

chr2-73450681-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000613296.6(ALMS1):c.4154C>G(p.Thr1385Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,610,408 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1385T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 67 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 86 hom. )

Consequence

ALMS1
ENST00000613296.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.411

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024403334).

BP6

Variant 2-73450681-C-G is Benign according to our data. Variant chr2-73450681-C-G is described in ClinVar as [Benign]. Clinvar id is 221015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0557 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.4154C>G	p.Thr1385Arg	missense_variant	8/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.4157C>G	p.Thr1386Arg	missense_variant	8/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.4154C>G	p.Thr1385Arg	missense_variant	8/23	1	NM_001378454.1	ENSP00000482968	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2462

AN:

148752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0577

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00624

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0144

Gnomad NFE

AF:

0.000239

Gnomad OTH

AF:

0.00891

GnomAD3 exomes

AF:

0.00410

AC:

1022

AN:

249200

Hom.:

AF XY:

0.00324

AC XY:

438

AN XY:

135176

show subpopulations

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:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000239

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00179

AC:

2611

AN:

1461530

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

1165

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0615

Gnomad4 AMR exome

AF:

0.00291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000130

Gnomad4 OTH exome

AF:

0.00399

GnomAD4 genome

AF:

0.0166

AC:

2467

AN:

148878

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1129

AN XY:

72656

show subpopulations

Gnomad4 AFR

AF:

0.0576

Gnomad4 AMR

AF:

0.00623

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000239

Gnomad4 OTH

AF:

0.00882

Alfa

AF:

0.00484

Hom.:

Bravo

AF:

0.0182

ESP6500AA

AF:

0.0553

AC:

206

ESP6500EA

AF:

0.000487

AC:

ExAC

AF:

0.00515

AC:

622

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Alstrom syndrome

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs115517108 in Alstrom syndrome yet. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Thr1384Arg in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 5.85% (573/9792) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115517108). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 08, 2019

ACMG criteria: BP4 (REVEL score 0.017 + 5 predictors, not using PP3/4 predictors), BA1 (5.7% in gnomAD African), BS2 (46 homozygotes in gnomAD), BP1 (most ALMS1 pathogenic variants are truncating)= benign -

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

AlphaMissense

Benign

0.034

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.024

DANN

Benign

0.12

DEOGEN2

Benign

0.0051

T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00041

LIST_S2

Benign

0.18

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.24

Sift4G

Benign

0.32

T;T;T

Vest4

0.092

MVP

0.076

ClinPred

0.00064

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.014

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