Variant 20-31514624-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178581.3(HM13):c.73C>T(p.Pro25Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HM13
NM_178581.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96

Variant links:

Genes affected

HM13 (HGNC:16435): (histocompatibility minor 13) The protein encoded by this gene, which localizes to the endoplasmic reticulum, catalyzes intramembrane proteolysis of some signal peptides after they have been cleaved from a preprotein. This activity is required to generate signal sequence-derived human lymphocyte antigen-E epitopes that are recognized by the immune system, and to process hepatitis C virus core protein. The encoded protein is an integral membrane protein with sequence motifs characteristic of the presenilin-type aspartic proteases. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HM13 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16038531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HM13	NM_178581.3 link	c.73C>T	p.Pro25Ser	missense_variant	1/13	ENST00000398174.9	NP_848696.1	Q8TCT9-2
HM13	NM_178580.3 link	c.73C>T	p.Pro25Ser	missense_variant	1/13		NP_848695.1	Q8TCT9-4
HM13	NM_030789.4 link	c.73C>T	p.Pro25Ser	missense_variant	1/12		NP_110416.1	Q8TCT9-1A0A0S2Z5V7
HM13	NM_178582.3 link	c.73C>T	p.Pro25Ser	missense_variant	1/3		NP_848697.1	Q8TCT9A0A0C4DGU3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HM13	ENST00000398174.9 link	c.73C>T	p.Pro25Ser	missense_variant	1/13	1	NM_178581.3	ENSP00000381237.3		Q8TCT9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000102

AC:

AN:

195170

Hom.:

AF XY:

0.00000938

AC XY:

AN XY:

106608

show subpopulations

Gnomad AFR exome

AF:

0.000179

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:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000209

AC:

AN:

1436878

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

712600

show subpopulations

Gnomad4 AFR exome

AF:

0.0000905

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The c.73C>T (p.P25S) alteration is located in exon 1 (coding exon 1) of the HM13 gene. This alteration results from a C to T substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.12

.;.;T;.;T;.

Eigen

Benign

0.027

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D;D;D;.;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.16

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.0

N;N;N;.;.;N

REVEL

Benign

0.057

Sift

Benign

0.73

T;T;T;.;.;T

Sift4G

Benign

0.86

T;T;T;.;T;T

Polyphen

0.90

P;P;P;.;.;.

Vest4

0.25

MutPred

0.25

Gain of phosphorylation at P25 (P = 0.0296);Gain of phosphorylation at P25 (P = 0.0296);Gain of phosphorylation at P25 (P = 0.0296);Gain of phosphorylation at P25 (P = 0.0296);Gain of phosphorylation at P25 (P = 0.0296);Gain of phosphorylation at P25 (P = 0.0296);

MVP

0.29

MPC

1.3

ClinPred

0.66

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.12

gMVP

0.52

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