2-73385903-TGGAGGAGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_001378454.1(ALMS1):c.72_74dupGGA(p.Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.38 ( 12015 hom., cov: 0)

Exomes 𝑓: 0.35 ( 3279 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-T-TGGA is Benign according to our data. Variant chr2-73385903-T-TGGA is described in ClinVar as Benign. ClinVar VariationId is 1206378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.72_74dupGGA	p.Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.72_74dupGGA	p.Glu25dup	disruptive_inframe_insertion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-225_-223dupTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-225_-223dupTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.72_74dupGGA	p.Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.379

AC:

54301

AN:

143200

Hom.:

12021

Cov.:

show subpopulations

Gnomad AFR

AF:

0.106

Gnomad AMI

AF:

0.633

Gnomad AMR

AF:

0.393

Gnomad ASJ

AF:

0.513

Gnomad EAS

AF:

0.559

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.503

Gnomad MID

AF:

0.518

Gnomad NFE

AF:

0.496

Gnomad OTH

AF:

0.415

GnomAD2 exomes

AF:

0.312

AC:

26026

AN:

83366

AF XY:

0.314

show subpopulations

Gnomad AFR exome

AF:

0.0853

Gnomad AMR exome

AF:

0.294

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.418

Gnomad FIN exome

AF:

0.306

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.342

GnomAD4 exome

AF:

0.347

AC:

192548

AN:

554346

Hom.:

3279

Cov.:

AF XY:

0.348

AC XY:

102997

AN XY:

295878

show subpopulations

African (AFR)

AF:

0.0931

AC:

1468

AN:

15772

American (AMR)

AF:

0.288

AC:

8912

AN:

30926

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

6337

AN:

17548

East Asian (EAS)

AF:

0.381

AC:

11611

AN:

30456

South Asian (SAS)

AF:

0.340

AC:

18830

AN:

55364

European-Finnish (FIN)

AF:

0.380

AC:

13737

AN:

36124

Middle Eastern (MID)

AF:

0.340

AC:

819

AN:

2412

European-Non Finnish (NFE)

AF:

0.358

AC:

120218

AN:

335784

Other (OTH)

AF:

0.354

AC:

10616

AN:

29960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

6898

13796

20694

27592

34490

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1012

2024

3036

4048

5060

<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:

0.379

AC:

54294

AN:

143306

Hom.:

12015

Cov.:

AF XY:

0.380

AC XY:

26431

AN XY:

69494

show subpopulations

African (AFR)

AF:

0.105

AC:

4209

AN:

39914

American (AMR)

AF:

0.393

AC:

5761

AN:

14664

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

1698

AN:

3310

East Asian (EAS)

AF:

0.560

AC:

2564

AN:

4578

South Asian (SAS)

AF:

0.477

AC:

2029

AN:

4250

European-Finnish (FIN)

AF:

0.503

AC:

4707

AN:

9350

Middle Eastern (MID)

AF:

0.515

AC:

136

AN:

264

European-Non Finnish (NFE)

AF:

0.496

AC:

31850

AN:

64184

Other (OTH)

AF:

0.416

AC:

818

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

1292

2584

3877

5169

6461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.372

Hom.:

1022

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Alstrom syndrome

Benign:2

Dec 12, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jul 07, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.37

Mutation Taster

=77/23

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