rs200266868

Positions:

chr2-73451989-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001378454.1(ALMS1):c.5462C>T(p.Pro1821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000162 in 1,613,398 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1821P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00063 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.66

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 -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.00670892).

BP6

Variant 2-73451989-C-T is Benign according to our data. Variant chr2-73451989-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241003.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000626 (95/151792) while in subpopulation AMR AF= 0.00321 (49/15274). AF 95% confidence interval is 0.00249. There are 1 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.5462C>T	p.Pro1821Leu	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.5465C>T	p.Pro1822Leu	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.5462C>T	p.Pro1821Leu	missense_variant	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000626

AC:

AN:

151672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000993

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000149

AC:

AN:

248964

Hom.:

AF XY:

0.000170

AC XY:

AN XY:

135148

show subpopulations

Gnomad AFR exome

AF:

0.000971

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000887

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000114

AC:

166

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000702

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000626

AC:

AN:

151792

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.000990

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000956

Hom.:

Bravo

AF:

0.000816

ESP6500AA

AF:

0.000814

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Apr 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1822 of the ALMS1 protein (p.Pro1822Leu). This variant is present in population databases (rs200266868, gnomAD 0.09%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Alstrom syndrome (PMID: 22876109). ClinVar contains an entry for this variant (Variation ID: 241003). 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 provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2024	Observed heterozygous with no other ALMS1 variant in a patient with Alstrom syndrome in published literature (PMID: 22876109); Observed in a patient with a diagnosis of blindness in published literature, although additional clinical information was not provided (PMID: 32483926); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32483926, 22876109, 31308072) -

Monogenic diabetes

Benign:1

Likely benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

May 19, 2017

ACMG criteria: PP3 (4 predictors), BP4 (5 predictors), BP1 (missense when truncating is disease causing)=likely benign -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 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

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

Sift4G

Uncertain

0.0030

D;D;D

Vest4

0.21

MVP

0.39

ClinPred

0.029

GERP RS

3.3

Varity_R

0.048

gMVP

0.22

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