NM_001378454.1:c.1126A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001378454.1(ALMS1):c.1126A>T(p.Thr376Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,612,786 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T376P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 2 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.34

Publications

1 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:

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=0.027503788).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000753 (110/1460570) while in subpopulation SAS AF = 0.000963 (83/86184). AF 95% confidence interval is 0.000796. There are 2 homozygotes in GnomAdExome4. There are 83 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.1126A>T	p.Thr376Ser	missense_variant	Exon 5 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.1126A>T	p.Thr376Ser	missense_variant	Exon 5 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.1126A>T	p.Thr376Ser	missense_variant	Exon 5 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

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:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000101

AC:

AN:

248598

AF XY:

0.000171

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000753

AC:

110

AN:

1460570

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

726396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.000963

AC:

AN:

86184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111098

Other (OTH)

AF:

0.0000166

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74364

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0556734), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

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:

0.0000565

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000116

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:2

Apr 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine with serine at codon 377 of the ALMS1 protein (p.Thr377Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs376750978, gnomAD 0.07%), including at least one homozygous and/or hemizygous individual. 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: 459847). 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 specified

Uncertain:1

Feb 26, 2020

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNA sequence analysis of the ALMS1 gene demonstrated a sequence change, c.1129A>T, in exon 5 that results in an amino acid change, p.Thr377Ser. This sequence change does not appear to have been previously described in patients with ALMS1-related disorders and has been described in the gnomAD database with a frequency of 0.07% in the South Asian sub-population (dbSNP rs376750978). The p.Thr377Ser change affects a poorly conserved amino acid residue located in a domain of the ALMS1 protein that is not known to be functional. The p.Thr377Ser substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr377Ser change remains unknown at this time. -

not provided

Uncertain:1

May 11, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as homozygous in two siblings of Saudi ancestry with Alstrom syndrome who were also homozygous for a nonsense variant in ALMS1; familial studies suggest the two variants may be present on the same allele (in cis) in each parent (Kamal et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(T376S) using alternate nomenclature; This variant is associated with the following publications: (PMID: Gosadi2021, 33981653, 31889847) -

Cardiovascular phenotype

Benign:1

Mar 13, 2025

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.13

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.27

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.0060

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.36

T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.028

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.20

.;N;.

PhyloP100

1.3

PrimateAI

Benign

0.31

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.039

MutPred

0.13

.;Loss of phosphorylation at T376 (P = 0.0522);Loss of phosphorylation at T376 (P = 0.0522);

MVP

0.21

ClinPred

0.027

GERP RS

1.7

Varity_R

0.024

gMVP

0.016

Mutation Taster

=100/0

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