Variant chr2-73385903-T-TGGAGGAGGAGGAGGAGGAGGAGGA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP3BP6

The NM_001378454.1(ALMS1):c.51_74dup(p.Glu21_Glu28dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000028 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

ALMS1
NM_001378454.1 inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.369

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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 id is 917603.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.51_74dup	p.Glu21_Glu28dup	inframe_insertion	1/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.51_74dup	p.Glu21_Glu28dup	inframe_insertion	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.51_74dup	p.Glu21_Glu28dup	inframe_insertion	1/23	1	NM_001378454.1	P3	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

Gnomad4 AFR exome

AF:

0.0000633

Gnomad4 AMR exome

AF:

0.0000320

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000978

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000110

Gnomad4 NFE exome

AF:

0.0000652

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000278

AC:

AN:

143636

Hom.:

Cov.:

AF XY:

0.0000431

AC XY:

AN XY:

69662

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000319

Gnomad4 NFE

AF:

0.0000155

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 23, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 06, 2020

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over