2-73385869-A-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001378454.1(ALMS1):c.1A>C(p.Met1?) variant causes a initiator codon 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 initiator_codon

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.27

Publications

5 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_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 46 pathogenic variants. Next in-frame start position is after 162 codons. Genomic position: 73419156. Lost 0.039 part of the original CDS.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALMS1	NM_001378454.1 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 23	ENST00000613296.6	NP_001365383.1
ALMS1	NM_015120.4 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 23		NP_055935.4	Q8TCU4
LOC105374804	XR_007087045.1 link	n.-188T>G		upstream_gene_variant
LOC105374804	XR_007087053.1 link	n.-188T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALMS1	ENST00000613296.6 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 23	1	NM_001378454.1	ENSP00000482968.1		Q8TCU4-1

Frequencies

GnomAD3 genomes

AF:

0.000557

AC:

AN:

148962

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000766

AC:

AN:

130518

AF XY:

0.0000142

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 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

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

African (AFR)

AF:

0.000123

AC:

AN:

16290

American (AMR)

AF:

0.0000877

AC:

AN:

34208

Ashkenazi Jewish (ASJ)

AF:

0.000460

AC:

AN:

19574

East Asian (EAS)

AF:

0.000225

AC:

AN:

31168

South Asian (SAS)

AF:

0.0000159

AC:

AN:

62780

European-Finnish (FIN)

AF:

0.000160

AC:

AN:

37488

Middle Eastern (MID)

AF:

0.000402

AC:

AN:

2488

European-Non Finnish (NFE)

AF:

0.000213

AC:

AN:

352380

Other (OTH)

AF:

0.000193

AC:

AN:

31012

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.237

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

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

African (AFR)

AF:

0.000268

AC:

AN:

41004

American (AMR)

AF:

0.000464

AC:

AN:

15084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3424

East Asian (EAS)

AF:

0.00251

AC:

AN:

4772

South Asian (SAS)

AF:

0.00267

AC:

AN:

4502

European-Finnish (FIN)

AF:

0.00199

AC:

AN:

10048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000284

AC:

AN:

66998

Other (OTH)

AF:

0.000482

AC:

AN:

2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.256

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alstrom syndrome

Uncertain:2

Mar 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Nov 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.3

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

PromoterAI

-0.68

Under-expression

(source)

Varity_R

0.59

gMVP

0.038

Mutation Taster

=44/156

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

2-73385869-A-C

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