Variant chr2-73385869-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PS1_Moderate

The NM_001378454.1(ALMS1):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALMS1
NM_001378454.1 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_001378454.1 (ALMS1) was described as [Likely_pathogenic] in ClinVar as 1064980

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALMS1	NM_001378454.1 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/23	ENST00000613296.6
ALMS1	NM_015120.4 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALMS1	ENST00000613296.6 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/23	1	NM_001378454.1	P3	Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148962

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000465

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.00267

Gnomad FIN

AF:

0.00199

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000284

Gnomad OTH

AF:

0.000487

GnomAD3 exomes

AF:

0.00000766

AC:

AN:

130518

Hom.:

AF XY:

0.0000142

AC XY:

AN XY:

70660

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:

0.00

Gnomad OTH exome

AF:

0.000250

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000187

AC:

110

AN:

587388

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

315852

show subpopulations

Gnomad4 AFR exome

AF:

0.000123

Gnomad4 AMR exome

AF:

0.0000877

Gnomad4 ASJ exome

AF:

0.000460

Gnomad4 EAS exome

AF:

0.000225

Gnomad4 SAS exome

AF:

0.0000159

Gnomad4 FIN exome

AF:

0.000160

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000193

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000550

AC:

AN:

149090

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

72784

show subpopulations

Gnomad4 AFR

AF:

0.000268

Gnomad4 AMR

AF:

0.000464

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.00267

Gnomad4 FIN

AF:

0.00199

Gnomad4 NFE

AF:

0.000284

Gnomad4 OTH

AF:

0.000482

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2022

This sequence change affects the initiator methionine of the ALMS1 mRNA. The next in-frame methionine is located at codon 163. This variant is present in population databases (no rsID available, gnomAD 0.004%). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.034

T;T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.80

MutPred

0.99

Gain of stability (P = 0.3811);Gain of stability (P = 0.3811);Gain of stability (P = 0.3811);

MVP

0.50

ClinPred

0.99

GERP RS

3.6

Varity_R

0.59

gMVP

0.038

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

Other links and lift over