2-73599494-C-T

Position:

chr2-73599494-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001378454.1(ALMS1):c.11641C>T(p.His3881Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,613,580 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 2 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:10

Conservation

PhyloP100: 2.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01774621).

BP6

Variant 2-73599494-C-T is Benign according to our data. Variant chr2-73599494-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240979.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (157/152274) while in subpopulation NFE AF= 0.00181 (123/68018). AF 95% confidence interval is 0.00155. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.11641C>T	p.His3881Tyr	missense_variant	17/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.11641C>T	p.His3881Tyr	missense_variant	17/23		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.11641C>T	p.His3881Tyr	missense_variant	17/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00181

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000964

AC:

240

AN:

248972

Hom.:

AF XY:

0.00103

AC XY:

139

AN XY:

135070

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.000280

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.00172

AC:

2512

AN:

1461306

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

1232

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000870

Gnomad4 FIN exome

AF:

0.000413

Gnomad4 NFE exome

AF:

0.00211

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.00103

AC:

157

AN:

152274

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00181

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000271

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00104

AC:

126

EpiCase

AF:

0.00202

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2022	Variant summary: ALMS1 c.11638C>T (p.His3880Tyr, also known as c.11644C>T in RefSeq) results in a 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 0.00097 in 280780 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European subpopulation is equal to the estimated maximal expected allele frequency for a pathogenic variant in in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy, strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.11638C>T has been reported in the literature in individuals affected with Alstrom Syndrome and Bardet-Biedl syndrome (Joy_2007, Pereiro_2010, Ozanturk_2015, Castro-Sanchez_2015, Chen_2017). These reports do not provide unequivocal conclusions about association of the variant with Alstrom Syndrome With Dilated Cardiomyopathy. In addition, co-occurrences with other pathogenic variants have been reported, one individual harbored BBS1 c.1169T>G (p.Met390Arg, homozygote, Castro-Sanchez_2015) and one individual carried BBS2 c.613-1G>C and BBS2 c.717+1G>A (Chen_2017), providing supporting evidence for a benign role. Functional studies report experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Alvarez-Satta_2017, Chen_2017). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 14, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 04, 2018	The p.His3880Tyr variant is classifed as likely benign because it has been ident ified in 0.17% (218/126250) of European chromosomes by gnomAD (http://gnomad.bro adinstitute.org), and computational prediction tools and conservation analysis s uggest that this variant may not impact the protein. Furthermore, although this variant has been reported in two individuals with features of Alstrom syndrome, both individuals harbored pathogenic variants in BBS1 and BBS2 indicating a diag nosis of Bardet-Biedl syndrome (Joy 2007, Chen 2017, Alvarez-Satta 2017). In vi tro functional studies performed in patient fibroblast cells indicate that the v ariant did not have an effect on the protein function (Chen 2017, Alvarez-Satta 2017). This variant is reported in ClinVar (Variation ID: 240979). In summary, t his variant meets criteria to be classified as likely benign. ACMG/AMP Criteria applied: BS1_Supporting, BP4, BP5, BS3_Supporting. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ALMS1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2021	This variant is associated with the following publications: (PMID: 18154657, 25846608, 28502102, 26082521, 28717663) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Alstrom syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2022	This sequence change replaces histidine with tyrosine at codon 3882 of the ALMS1 protein (p.His3882Tyr). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs142278066, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with an ALMS1-related disease. However, in one of these individuals the variant was found to co-occur with 2 pathogenic variants in the BBS2 gene. (PMID: 18154657, 28502102). ClinVar contains an entry for this variant (Variation ID: 240979). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Feb 15, 2019

ACMG criteria: BP4 (REVEL 0.042 + 5 predictors), BP1 (missense in gene where truncating variants are mechanism of disease), PM3 (PMID:18154657 reported a compound het AS patient also carrying V424I) = likely benign -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2021

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

0.094

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.34

Sift4G

Uncertain

0.013

D;D

Vest4

0.28

MVP

0.23

ClinPred

0.0060

GERP RS

3.9

Varity_R

0.065

gMVP

0.097

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