rs373286582

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001378454.1(ALMS1):c.6299A>T(p.Lys2100Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K2100K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.67

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11036566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.6299A>T	p.Lys2100Ile	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.6302A>T	p.Lys2101Ile	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.6299A>T	p.Lys2100Ile	missense_variant	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247754

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134590

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000972

AC:

142

AN:

1461530

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000123

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000245

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 18, 2022	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 2101 of the ALMS1 protein (p.Lys2101Ile). This variant is present in population databases (rs373286582, gnomAD 0.005%). 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: 403933). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Program, Stanford Medicine	Jul 02, 2021	The p.Lys2101Ile variant (also referred to as p.Lys2099Ile) in the ALMS1gene has not been previously reported in association with disease. This variant has been identified in 5/112,154 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/).•Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Lys2101Ile variant is uncertain. Additional information is needed to resolve the significance of this variant.[ACMG evidence codes used: PM2; BP4] -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 13, 2017

Variant summary: The ALMS1 c.6296A>T (p.Lys2099Ile, alternative name c.6302A>T) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/5 in silico tools. This variant was found in 4/118064 control chromosomes from ExAC, only observed in the European (Non-Finnish) subpopulation at a frequency of 0.000062 (4/65004). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Oct 12, 2016

The testing laboratory was Invitae. Given that there is no case data available on this variant, and that it is present in control populations, we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy individuals (â€œpredictive genetic testingâ€). Notably, the gene does not match the patientâ€™s phenotype. The ALMS1 gene is associated with autosomal recessive AlstrÃ¶m syndrome. To our knowledge, there are no case reports of LVNC caused by a heterozygous variant in ALMS1. There is no case data for this variant. Furthermore, loss-of-function variants in ALMS1, such as frameshift, splice site and truncating, are the most likely to cause disease. There is little evidence that missense changes, such as that of our patient, would have a clinically significant impact. The in silico prediction model SIFT predicts this variant to be deleterious. The lysine at codon 2101 is not conserved across species. There are multiple Ensemble transcripts for this gene and only one HGVS transcript. The testing lab uses a different Ensembl transcript for this gene than that which directly corresponds to the HGVS transcript (NM_015120.4 corresponds with ENST00000264448 using Mutation taster). According to the ENST00000264448 transcript, this variant would be reported as p.Lys2099Ile. The variant, using notation p.Lys2099Ile and the ENST00000264448 transcript, is present in 4 out of 59,032 individuals the ExAC dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Specifically, this variant is present in 4 out of 32,502 individuals of European (non-Finnish) descent. The average coverage at that site in ExAC is 30x. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2019

The p.K2101I variant (also known as c.6302A>T), located in coding exon 8 of the ALMS1 gene, results from an A to T substitution at nucleotide position 6302. The lysine at codon 2101 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.25

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.17

T;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

Sift4G

Uncertain

0.013

D;D;D

Vest4

0.22

MVP

0.36

ClinPred

0.88

GERP RS

1.8

Varity_R

0.18

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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