chr2-73385903-T-TGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS1

The NM_001378454.1(ALMS1):c.57_74dupGGAGGAGGAGGAGGAGGA(p.Glu20_Glu25dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E25E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-T-TGGAGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000285 (41/143626) while in subpopulation EAS AF = 0.00131 (6/4580). AF 95% confidence interval is 0.00057. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.57_74dupGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.57_74dupGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-240_-223dupTCCTCCTCCTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-240_-223dupTCCTCCTCCTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.57_74dupGGAGGAGGAGGAGGAGGA	p.Glu20_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000286

AC:

AN:

143522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000100

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000681

Gnomad ASJ

AF:

0.00151

Gnomad EAS

AF:

0.00131

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000373

Gnomad OTH

AF:

0.000512

GnomAD4 exome

AF:

0.000312

AC:

174

AN:

557704

Hom.:

Cov.:

AF XY:

0.000299

AC XY:

AN XY:

297814

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15794

American (AMR)

AF:

0.0000640

AC:

AN:

31236

Ashkenazi Jewish (ASJ)

AF:

0.00102

AC:

AN:

17636

East Asian (EAS)

AF:

0.00124

AC:

AN:

30670

South Asian (SAS)

AF:

0.000143

AC:

AN:

55942

European-Finnish (FIN)

AF:

0.0000275

AC:

AN:

36320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.000290

AC:

AN:

337568

Other (OTH)

AF:

0.000299

AC:

AN:

30116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.336

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000285

AC:

AN:

143626

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

69658

show subpopulations

African (AFR)

AF:

0.000100

AC:

AN:

39970

American (AMR)

AF:

0.0000680

AC:

AN:

14700

Ashkenazi Jewish (ASJ)

AF:

0.00151

AC:

AN:

3318

East Asian (EAS)

AF:

0.00131

AC:

AN:

4580

South Asian (SAS)

AF:

0.00

AC:

AN:

4264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000373

AC:

AN:

64332

Other (OTH)

AF:

0.000507

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

1022

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 02, 2020

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The variant in ALMS1, c.60_74dup15 (p.Glu24_Glu28dup) results in an in-frame duplication in a Glu repetitive region of the ALMS1 protein (Glu13_Glu28). The variant was absent in 83366 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.60_74dup15 in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Furthermore, there are no reports of other variants in this Glu repetitive region in the HGMD database. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Oher duplication variants located in this Glu repetitive region (examples: p.Glu26_Glu28dup, p.Glu23_Glu24dup, p.Glu24dup) have been classified as benign by our laboratory. Based on the evidence outlined above, the variant was classified as likely benign. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 28, 2019

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

(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