rs200586877

Positions:

chr2-73491348-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_001378454.1(ALMS1):c.9389C>G(p.Pro3130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,614,160 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 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

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 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=0.037063777).

BP6

Variant 2-73491348-C-G is Benign according to our data. Variant chr2-73491348-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_risk_allele=1, Uncertain_significance=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.9389C>G	p.Pro3130Arg	missense_variant	10/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.9392C>G	p.Pro3131Arg	missense_variant	10/23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.9389C>G	p.Pro3130Arg	missense_variant	10/23	1	NM_001378454.1	ENSP00000482968	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000160

AC:

AN:

249458

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000336

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000274

AC:

401

AN:

1461856

Hom.:

Cov.:

AF XY:

0.000249

AC XY:

181

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000351

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000164

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000246

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000732

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:3Other:1

Uncertain risk allele, 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 rs200586877 in Alstrom syndrome yet. -
Uncertain significance, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3131 of the ALMS1 protein (p.Pro3131Arg). This variant is present in population databases (rs200586877, gnomAD 0.03%). 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: 393378). 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 24, 2020	The p.Pro3131Arg variant in ALMS1 has not been previously reported in individuals with hearing loss, but has been identified in 0.03% (46/128626) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 393378). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 25, 2019	Variant summary: The variant, ALMS1 c.9386C>G (p.Pro3129Arg, also known as c.9392C>G) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 277096 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00016 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9386C>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Uncertain Significance X2 ; Likely benign X1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2024

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

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: BP4 (REVEL 0.037 + 7 predictors), BP1 (missense variant when truncating case disease)=likely benign -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2022

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

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.030

T;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.88

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

Sift4G

Uncertain

0.0070

D;D;D

Vest4

0.14

MVP

0.24

ClinPred

0.035

GERP RS

2.1

Varity_R

0.059

gMVP

0.053

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