NM_001378454.1:c.4244G>C

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.4244G>C(p.Gly1415Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,607,392 control chromosomes in the GnomAD database, including 66,432 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1415D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 15837 hom., cov: 31)

Exomes 𝑓: 0.24 ( 50595 hom. )

Consequence

ALMS1
NM_001378454.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.83

Publications

35 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=8.505922E-7).

BP6

Variant 2-73450771-G-C is Benign according to our data. Variant chr2-73450771-G-C is described in ClinVar as Benign. ClinVar VariationId is 379229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.4244G>C	p.Gly1415Ala	missense_variant	Exon 8 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.4244G>C	p.Gly1415Ala	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.4244G>C	p.Gly1415Ala	missense_variant	Exon 8 of 23	1	NM_001378454.1	ENSP00000482968.1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

58505

AN:

146478

Hom.:

15774

Cov.:

show subpopulations

Gnomad AFR

AF:

0.773

Gnomad AMI

AF:

0.286

Gnomad AMR

AF:

0.385

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00808

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.262

Gnomad MID

AF:

0.258

Gnomad NFE

AF:

0.248

Gnomad OTH

AF:

0.350

GnomAD2 exomes

AF:

0.268

AC:

66158

AN:

247308

AF XY:

0.250

show subpopulations

Gnomad AFR exome

AF:

0.784

Gnomad AMR exome

AF:

0.412

Gnomad ASJ exome

AF:

0.171

Gnomad EAS exome

AF:

0.00620

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.238

Gnomad OTH exome

AF:

0.246

GnomAD4 exome

AF:

0.243

AC:

355637

AN:

1460804

Hom.:

50595

Cov.:

AF XY:

0.239

AC XY:

173873

AN XY:

726718

show subpopulations

African (AFR)

AF:

0.781

AC:

26143

AN:

33468

American (AMR)

AF:

0.409

AC:

18244

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.169

AC:

4415

AN:

26094

East Asian (EAS)

AF:

0.0123

AC:

485

AN:

39574

South Asian (SAS)

AF:

0.167

AC:

14383

AN:

86054

European-Finnish (FIN)

AF:

0.232

AC:

12372

AN:

53406

Middle Eastern (MID)

AF:

0.244

AC:

1407

AN:

5762

European-Non Finnish (NFE)

AF:

0.237

AC:

263187

AN:

1111496

Other (OTH)

AF:

0.249

AC:

15001

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

16273

32546

48818

65091

81364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9036

18072

27108

36144

45180

<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:

0.400

AC:

58633

AN:

146588

Hom.:

15837

Cov.:

AF XY:

0.394

AC XY:

28146

AN XY:

71466

show subpopulations

African (AFR)

AF:

0.773

AC:

31755

AN:

41070

American (AMR)

AF:

0.385

AC:

5687

AN:

14762

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

603

AN:

3334

East Asian (EAS)

AF:

0.00810

AC:

AN:

4570

South Asian (SAS)

AF:

0.164

AC:

726

AN:

4440

European-Finnish (FIN)

AF:

0.262

AC:

2563

AN:

9786

Middle Eastern (MID)

AF:

0.269

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.248

AC:

16245

AN:

65496

Other (OTH)

AF:

0.348

AC:

708

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1369

2738

4107

5476

6845

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:

0.220

Hom.:

3098

Bravo

AF:

0.415

TwinsUK

AF:

0.230

AC:

851

ALSPAC

AF:

0.233

AC:

898

ESP6500AA

AF:

0.738

AC:

2767

ESP6500EA

AF:

0.238

AC:

1956

ExAC

AF:

0.268

AC:

32390

Asia WGS

AF:

0.126

AC:

438

AN:

3478

EpiCase

AF:

0.233

EpiControl

AF:

0.238

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.Gly1414Ala in exon 8 of ALMS1: This variant is not expected to have clinical s ignificance because it has been identified in 87.82% (1161/1322) of African chro mosomes by the 1000 Genomes Project (Phase 3; dbSNP rs6546837).

Sep 22, 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.

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

0.051

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.0020

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.0059

T;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00028

LIST_S2

Benign

0.086

T;T;T

MetaRNN

Benign

8.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

-2.8

PrimateAI

Benign

0.23

PROVEAN

Benign

0.0

.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.

Sift4G

Benign

0.80

T;T;T

Vest4

0.020

ClinPred

0.0067

GERP RS

-0.18

Varity_R

0.028

gMVP

0.017

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