NM_001378454.1:c.69_74dupGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BA1

The NM_001378454.1(ALMS1):c.69_74dupGGAGGA(p.Glu24_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.059 ( 291 hom., cov: 0)

Exomes 𝑓: 0.063 ( 154 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:12

Conservation

PhyloP100: 0.369

Publications

7 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:

ENSG00000285068 (HGNC:):

ENSG00000285068 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-T-TGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218713.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-228_-223dupTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-228_-223dupTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.69_74dupGGAGGA	p.Glu24_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0595

AC:

8536

AN:

143400

Hom.:

292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0228

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.0698

Gnomad EAS

AF:

0.0755

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0617

Gnomad MID

AF:

0.0603

Gnomad NFE

AF:

0.0672

Gnomad OTH

AF:

0.0595

GnomAD2 exomes

AF:

0.0668

AC:

5566

AN:

83366

AF XY:

0.0657

show subpopulations

Gnomad AFR exome

AF:

0.0205

Gnomad AMR exome

AF:

0.115

Gnomad ASJ exome

AF:

0.0393

Gnomad EAS exome

AF:

0.0629

Gnomad FIN exome

AF:

0.0320

Gnomad NFE exome

AF:

0.0484

Gnomad OTH exome

AF:

0.0477

GnomAD4 exome

AF:

0.0632

AC:

35210

AN:

557130

Hom.:

154

Cov.:

AF XY:

0.0645

AC XY:

19197

AN XY:

297462

show subpopulations

African (AFR)

AF:

0.0218

AC:

345

AN:

15792

American (AMR)

AF:

0.106

AC:

3314

AN:

31164

Ashkenazi Jewish (ASJ)

AF:

0.0554

AC:

977

AN:

17620

East Asian (EAS)

AF:

0.0749

AC:

2295

AN:

30636

South Asian (SAS)

AF:

0.0967

AC:

5400

AN:

55846

European-Finnish (FIN)

AF:

0.0494

AC:

1792

AN:

36292

Middle Eastern (MID)

AF:

0.0665

AC:

161

AN:

2422

European-Non Finnish (NFE)

AF:

0.0566

AC:

19101

AN:

337270

Other (OTH)

AF:

0.0607

AC:

1825

AN:

30088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.409

Heterozygous variant carriers

1727

3454

5181

6908

8635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

360

540

720

900

<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:

0.0594

AC:

8530

AN:

143504

Hom.:

291

Cov.:

AF XY:

0.0622

AC XY:

4327

AN XY:

69588

show subpopulations

African (AFR)

AF:

0.0227

AC:

908

AN:

39946

American (AMR)

AF:

0.105

AC:

1537

AN:

14686

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

232

AN:

3322

East Asian (EAS)

AF:

0.0753

AC:

345

AN:

4580

South Asian (SAS)

AF:

0.112

AC:

475

AN:

4256

European-Finnish (FIN)

AF:

0.0617

AC:

579

AN:

9386

Middle Eastern (MID)

AF:

0.0602

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0672

AC:

4322

AN:

64268

Other (OTH)

AF:

0.0589

AC:

116

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

327

654

982

1309

1636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0447

Hom.:

1022

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:5Benign:2

Nov 12, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:7

Jun 23, 2015

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 03, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 07, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 19, 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

PhyloP100

0.37

Mutation Taster

=78/22

polymorphism (auto)

(source)

Splicing

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