chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_001378454.1(ALMS1):c.51_74dupGGAGGAGGAGGAGGAGGAGGAGGA(p.Glu18_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 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 0.000028 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

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: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001378454.1

BP6

Variant 2-73385903-T-TGGAGGAGGAGGAGGAGGAGGAGGA is Benign according to our data. Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 917603.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.51_74dupGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu18_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.51_74dupGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu18_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-246_-223dupTCCTCCTCCTCCTCCTCCTCCTCC		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-246_-223dupTCCTCCTCCTCCTCCTCCTCCTCC		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.51_74dupGGAGGAGGAGGAGGAGGAGGAGGA	p.Glu18_Glu25dup	disruptive_inframe_insertion	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.0000279

AC:

AN:

143532

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000319

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000574

AC:

AN:

557738

Hom.:

Cov.:

AF XY:

0.0000369

AC XY:

AN XY:

297828

show subpopulations

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

African (AFR)

AF:

0.0000633

AC:

AN:

15796

American (AMR)

AF:

0.0000320

AC:

AN:

31236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17646

East Asian (EAS)

AF:

0.0000978

AC:

AN:

30670

South Asian (SAS)

AF:

0.00

AC:

AN:

55944

European-Finnish (FIN)

AF:

0.000110

AC:

AN:

36320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2422

European-Non Finnish (NFE)

AF:

0.0000652

AC:

AN:

337586

Other (OTH)

AF:

0.0000332

AC:

AN:

30118

⚠️ 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: 0.275

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:

0.0000278

AC:

AN:

143636

Hom.:

Cov.:

AF XY:

0.0000431

AC XY:

AN XY:

69662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39970

American (AMR)

AF:

0.00

AC:

AN:

14700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3322

East Asian (EAS)

AF:

0.00

AC:

AN:

4584

South Asian (SAS)

AF:

0.00

AC:

AN:

4264

European-Finnish (FIN)

AF:

0.000319

AC:

AN:

9398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64334

Other (OTH)

AF:

0.00

AC:

AN:

1972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

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

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

ALMS1-related disorder

Uncertain:1

Jun 23, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ALMS1 c.54_74dup21 variant is predicted to result in an in-frame duplication (p.Glu22_Glu28dup). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Alstrom syndrome

Uncertain:1

Jun 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.54_77dup, results in the insertion of 8 amino acid(s) of the ALMS1 protein (p.Glu22_Glu29dup), but otherwise preserves the integrity of the reading frame. -

not specified

Benign:1

Jan 06, 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 ALMS1 variant, c.54_74dup21 (p.Glu22_Glu28dup) is located in a Glu repetitive region (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. No variants located in this Glu repetitive region were reported in HGMD database and other variants (including deletion and duplication) located in this repetitive region were reported in LOVD database and classified as likely benign/benign. In addition, other duplication variants (p.Glu26_Glu28dup, p.Glu23_Glu24dup, p.Glu24dup) located in this Glu repetitive region have been classified as benign by our laboratory. To our knowledge, no occurrence of c.54_74dup21 in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

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