rs201074268

Positions:

chr2-73449838-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378454.1(ALMS1):c.3311G>A(p.Gly1104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,028 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1104S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 10 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.53

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048203766).

BP6

Variant 2-73449838-G-A is Benign according to our data. Variant chr2-73449838-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 387328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.002 (305/152232) while in subpopulation NFE AF= 0.00284 (193/68010). AF 95% confidence interval is 0.00251. There are 1 homozygotes in gnomad4. There are 172 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.3311G>A	p.Gly1104Asp	missense_variant	8/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.3314G>A	p.Gly1105Asp	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.3311G>A	p.Gly1104Asp	missense_variant	8/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00201

AC:

305

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00197

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00395

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00284

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00188

AC:

468

AN:

248562

Hom.:

AF XY:

0.00197

AC XY:

266

AN XY:

134838

show subpopulations

Gnomad AFR exome

AF:

0.000324

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00385

Gnomad NFE exome

AF:

0.00264

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00285

AC:

4172

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1971

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00346

Gnomad4 NFE exome

AF:

0.00331

Gnomad4 OTH exome

AF:

0.00278

GnomAD4 genome

AF:

0.00200

AC:

305

AN:

152232

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00395

Gnomad4 NFE

AF:

0.00284

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00260

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00168

AC:

203

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 05, 2019	- -
Benign, 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 rs201074268 in Alstrom syndrome yet. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2022	Variant summary: ALMS1 c.3308G>A/p.Gly1103Asp (also known as c.3314G>A in RefSeq) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 248562 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although the variant has been reported in a paper describing the mutational spectrum of Alstrom syndrome, this publication provides no primary evidence supporting a pathogenic outcome (Marshall_2015). To our knowledge, no occurrence of c.3308G>A in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (TTR c.424G>A , p.Val1421Ile), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ALMS1: BP4 -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 25, 2019

ACMG criteria: BP4 (8 predictors + REVEL score 0.117), BS2 (1 homozygotes in gnomAD), BP1 (missense when truncating are cause of disease)= benign -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2019

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

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.0020

DANN

Benign

0.30

DEOGEN2

Benign

0.014

T;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.038

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.22

Sift4G

Benign

0.48

T;T;T

Vest4

0.14

MVP

0.088

ClinPred

0.0075

GERP RS

-8.9

Varity_R

0.055

gMVP

0.040

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