Variant rs757722767 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001378454.1(ALMS1):c.11809dupA(p.Met3937fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALMS1
NM_001378454.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 1.64

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:

ALMS1 (HGNC:):

ALMS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-73600814-G-GA is Pathogenic according to our data. Variant chr2-73600814-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.11809dupA	p.Met3937fs	frameshift_variant	18/23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 linkuse as main transcript	c.11809dupA	p.Met3937fs	frameshift_variant	18/23		NP_055935.4	Q8TCU4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.11809dupA	p.Met3937fs	frameshift_variant	18/23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251088

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, Motol Hospital	Nov 20, 2024	This variant was detected in a proband (male) with visual defects (achromatopsia), together in trans with a variant NM_015120.4(ALMS1):c.5283del. The segregation analysis confirmed the paternal origin of the reported variant NM_015120.4(ALMS1):c.11812dup and maternal origin of the variant NM_015120.4(ALMS1):c.5283del in proband. The pathogenic/likely pathogenic variants affecting the ALMS1 gene are well documented as a molecular cause of autosomal recessive "Alstrom syndrome" (OMIM:203800) (PMID:36927560;11941369;11941370;17594715). To conclude, the variant is classified as pathogenic (ACMG PVS1, PM2, PM3). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 550296). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 25846608). This variant is present in population databases (rs757722767, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Met3938Asnfs*8) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

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