2-73602245-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001378454.1(ALMS1):c.12175C>T(p.Leu4059Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,824 control chromosomes in the GnomAD database, including 62,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L4059L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.37 ( 13995 hom., cov: 32)

Exomes 𝑓: 0.24 ( 48469 hom. )

Consequence

ALMS1
NM_001378454.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.33

Publications

24 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 2-73602245-C-T is Benign according to our data. Variant chr2-73602245-C-T is described in ClinVar as Benign. ClinVar VariationId is 383765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.12175C>T	p.Leu4059Leu	synonymous_variant	Exon 20 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55947

AN:

151940

Hom.:

13938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.00715

Gnomad SAS

AF:

0.148

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.238

Gnomad OTH

AF:

0.323

GnomAD2 exomes

AF:

0.260

AC:

65253

AN:

251166

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.722

Gnomad AMR exome

AF:

0.402

Gnomad ASJ exome

AF:

0.151

Gnomad EAS exome

AF:

0.00566

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.235

Gnomad OTH exome

AF:

0.236

GnomAD4 exome

AF:

0.240

AC:

351385

AN:

1461766

Hom.:

48469

Cov.:

AF XY:

0.236

AC XY:

171876

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.715

AC:

23929

AN:

33478

American (AMR)

AF:

0.402

AC:

17972

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3957

AN:

26132

East Asian (EAS)

AF:

0.0118

AC:

469

AN:

39696

South Asian (SAS)

AF:

0.166

AC:

14276

AN:

86252

European-Finnish (FIN)

AF:

0.231

AC:

12333

AN:

53416

Middle Eastern (MID)

AF:

0.236

AC:

1364

AN:

5768

European-Non Finnish (NFE)

AF:

0.236

AC:

262482

AN:

1111908

Other (OTH)

AF:

0.242

AC:

14603

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

14813

29626

44440

59253

74066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8996

17992

26988

35984

44980

<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:

0.369

AC:

56067

AN:

152058

Hom.:

13995

Cov.:

AF XY:

0.363

AC XY:

26980

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.710

AC:

29418

AN:

41460

American (AMR)

AF:

0.366

AC:

5599

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.158

AC:

550

AN:

3472

East Asian (EAS)

AF:

0.00716

AC:

AN:

5164

South Asian (SAS)

AF:

0.149

AC:

719

AN:

4826

European-Finnish (FIN)

AF:

0.243

AC:

2566

AN:

10566

Middle Eastern (MID)

AF:

0.224

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.238

AC:

16179

AN:

67968

Other (OTH)

AF:

0.319

AC:

674

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1444

2888

4331

5775

7219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.280

Hom.:

13684

Bravo

AF:

0.394

Asia WGS

AF:

0.118

AC:

409

AN:

3478

EpiCase

AF:

0.230

EpiControl

AF:

0.235

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -

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

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

- -

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.Leu4058Leu in exon 20 of ALMS1: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 80.11% (1059/1322) of African chromosomes by the 1000 Genomes Project (Phase 3; dbSNP rs1052162). -

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

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

- -

Jul 14, 2021

Genome-Nilou Lab

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

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.1

(source)

DANN

Benign

0.91

PhyloP100

2.3

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