Variant chr17-46923193-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_004287.5(GOSR2):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,393,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GOSR2
NM_004287.5 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

GOSR2 (HGNC:4431): (golgi SNAP receptor complex member 2) This gene encodes a trafficking membrane protein which transports proteins among the medial- and trans-Golgi compartments. Due to its chromosomal location and trafficking function, this gene may be involved in familial essential hypertension. [provided by RefSeq, Mar 2016]

GOSR2 links:

LRRC37A2 (HGNC:):

LRRC37A2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-46923193-A-C is Pathogenic according to our data. Variant chr17-46923193-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2501009.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GOSR2	NM_004287.5 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/6	ENST00000640051.2	NP_004278.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GOSR2	ENST00000640051.2 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	1/6	1	NM_004287.5	ENSP00000492751	P3	O14653-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000648

AC:

AN:

154342

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81628

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:

0.0000169

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1393566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687694

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:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000564

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

King Laboratory, University of Washington

Apr 17, 2023

GOSR2 c.1A>C, p.Met1Leu is homozygous in four Palestinian children with congenital recessive profound hearing loss with no severe syndromic features, and heterozygous or not present in their unaffected parents and siblings. GOSR2 c.1A>C protein levels are reduced to ~5% of normal levels. The variant is not seen in any of ~2000 controls of Palestinian ancestry and as of April 2023, this variant has not been reported to ClinVar and is found in one heterozygote on gnomAD v3. (Aburayyan, Carlson, et al. Hum Molec Genet. 2023; PMID 30704134). -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.22

.;.;.;.;.;.;T;.;.;.;.;.;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.53

MutationTaster

Benign

1.0

D;D;D;D;D;D

PROVEAN

Uncertain

-2.5

.;.;.;D;D;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.50

Sift

Pathogenic

0.0

.;.;.;D;D;.;.;.;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;D;D;D;.;.;.;.;D;.;.;.

Polyphen

0.76, 0.36

.;.;.;P;.;.;B;.;.;.;.;.;.;.

Vest4

0.56, 0.56, 0.55, 0.53

MutPred

0.81

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.85

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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