2-73449619-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001378454.1(ALMS1):c.3092C>G(p.Thr1031Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00036 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1031A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00037 ( 1 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -1.49

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Alstrom syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Orphanet, Genomics England PanelApp

ALMS1 links:

ENSG00000295621 (HGNC:):

ENSG00000295621 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013459861).

BP6

Variant 2-73449619-C-G is Benign according to our data. Variant chr2-73449619-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198870.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000374 (547/1461800) while in subpopulation SAS AF = 0.000974 (84/86256). AF 95% confidence interval is 0.000805. There are 1 homozygotes in GnomAdExome4. There are 273 alleles in the male GnomAdExome4 subpopulation. Median coverage is 40. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.3092C>G	p.Thr1031Ser	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.3092C>G	p.Thr1031Ser	missense_variant	Exon 8 of 23		NP_055935.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.3092C>G	p.Thr1031Ser	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000269

AC:

AN:

248790

AF XY:

0.000296

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000374

AC:

547

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.0000447

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000974

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000390

AC:

434

AN:

1111956

Other (OTH)

AF:

0.000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

105

140

175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000223

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000852

AC:

ExAC

AF:

0.000339

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Apr 22, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 17, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Alstrom syndrome

Uncertain:1Benign:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1032 of the ALMS1 protein (p.Thr1032Ser). This variant is present in population databases (rs199922877, gnomAD 0.09%). 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: 198870). 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 serine 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.

May 02, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Oct 29, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.52

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.058

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0054

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.14

T;T;T

M_CAP

Benign

0.0045

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

-1.5

PrimateAI

Benign

0.24

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Benign

1.0

T;T;T

Vest4

0.053

ClinPred

0.0045

GERP RS

-1.7

PromoterAI

-0.0010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.031

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over