NM_001378454.1:c.1174C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.1174C>T(p.Arg392Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,606,736 control chromosomes in the GnomAD database, including 66,086 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R392S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.39 ( 15844 hom., cov: 32)

Exomes 𝑓: 0.24 ( 50242 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0890

Publications

40 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.4957634E-7).

BP6

Variant 2-73424839-C-T is Benign according to our data. Variant chr2-73424839-C-T is described in ClinVar as Benign. ClinVar VariationId is 383753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.1174C>T	p.Arg392Cys	missense_variant	Exon 5 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.1174C>T	p.Arg392Cys	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.1174C>T	p.Arg392Cys	missense_variant	Exon 5 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.385

AC:

58555

AN:

151916

Hom.:

15781

Cov.:

show subpopulations

Gnomad AFR

AF:

0.767

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.372

Gnomad ASJ

AF:

0.175

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.210

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.338

GnomAD2 exomes

AF:

0.266

AC:

65285

AN:

245640

AF XY:

0.248

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.407

Gnomad ASJ exome

AF:

0.173

Gnomad EAS exome

AF:

0.00614

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.236

Gnomad OTH exome

AF:

0.242

GnomAD4 exome

AF:

0.243

AC:

353524

AN:

1454702

Hom.:

50242

Cov.:

AF XY:

0.239

AC XY:

172639

AN XY:

722594

show subpopulations

African (AFR)

AF:

0.780

AC:

25946

AN:

33250

American (AMR)

AF:

0.407

AC:

18020

AN:

44254

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

4425

AN:

25910

East Asian (EAS)

AF:

0.0123

AC:

486

AN:

39570

South Asian (SAS)

AF:

0.167

AC:

14282

AN:

85472

European-Finnish (FIN)

AF:

0.231

AC:

12295

AN:

53182

Middle Eastern (MID)

AF:

0.244

AC:

1397

AN:

5722

European-Non Finnish (NFE)

AF:

0.236

AC:

261768

AN:

1107282

Other (OTH)

AF:

0.248

AC:

14905

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

12490

24981

37471

49962

62452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9018

18036

27054

36072

45090

<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:

0.386

AC:

58681

AN:

152034

Hom.:

15844

Cov.:

AF XY:

0.379

AC XY:

28175

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.767

AC:

31822

AN:

41476

American (AMR)

AF:

0.373

AC:

5693

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.175

AC:

606

AN:

3470

East Asian (EAS)

AF:

0.00715

AC:

AN:

5174

South Asian (SAS)

AF:

0.150

AC:

721

AN:

4804

European-Finnish (FIN)

AF:

0.243

AC:

2561

AN:

10550

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.239

AC:

16226

AN:

67964

Other (OTH)

AF:

0.334

AC:

707

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1384

2769

4153

5538

6922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

476

952

1428

1904

2380

<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:

0.275

Hom.:

34555

Bravo

AF:

0.414

TwinsUK

AF:

0.229

AC:

848

ALSPAC

AF:

0.233

AC:

897

ESP6500AA

AF:

0.737

AC:

2778

ESP6500EA

AF:

0.237

AC:

1953

ExAC

AF:

0.268

AC:

32310

Asia WGS

AF:

0.123

AC:

430

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 09, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg392Cys in exon 5 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 87.82% (1161/1322) of African chrom osomes by the 1000 Genomes Project (Phase 3; dbSNP rs3813227). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alstrom syndrome

Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

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

0.061

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

3.2

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.0060

T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0019

LIST_S2

Benign

0.32

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

.;N;.

PhyloP100

0.089

PrimateAI

Benign

0.24

Sift4G

Benign

0.57

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.064

ClinPred

0.00046

GERP RS

0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.021

Mutation Taster

=100/0

polymorphism (auto)

(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