chr2-73448592-A-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001378454.1(ALMS1):c.2065A>G(p.Thr689Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000455 in 1,613,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: -0.492

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05889699).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000369 (56/151914) while in subpopulation NFE AF= 0.000662 (45/67982). AF 95% confidence interval is 0.000508. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.2065A>G	p.Thr689Ala	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.2065A>G	p.Thr689Ala	missense_variant	Exon 8 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.2065A>G	p.Thr689Ala	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000369

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000662

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000261

AC:

AN:

248908

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

135002

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000497

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000464

AC:

679

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000448

AC XY:

326

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000582

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000369

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.000337

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000662

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000494

Hom.:

Bravo

AF:

0.000348

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000606

AC:

ExAC

AF:

0.000215

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Alstrom syndrome

Uncertain:3

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 690 of the ALMS1 protein (p.Thr690Ala). This variant is present in population databases (rs201804994, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 240985). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Sep 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ALMS1 c.2062A>G (p.Thr688Ala), alternate nomenclature p.Thr689Ala/p.Thr690Ala, results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 248908 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Alstrom Syndrome (0.00026 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2062A>G in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 240985). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype

Benign:1

Apr 21, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.038

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.65

T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.30

Sift4G

Uncertain

0.043

D;D;T

Vest4

0.20

MVP

0.055

ClinPred

0.046

GERP RS

-8.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.043

gMVP

0.082

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