Variant 20-31514646-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_178581.3(HM13):c.95T>C(p.Ile32Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,574,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

HM13
NM_178581.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.98

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18386728).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HM13	NM_178581.3 link	c.95T>C	p.Ile32Thr	missense_variant	1/13	ENST00000398174.9	NP_848696.1	Q8TCT9-2
HM13	NM_178580.3 link	c.95T>C	p.Ile32Thr	missense_variant	1/13		NP_848695.1	Q8TCT9-4
HM13	NM_030789.4 link	c.95T>C	p.Ile32Thr	missense_variant	1/12		NP_110416.1	Q8TCT9-1A0A0S2Z5V7
HM13	NM_178582.3 link	c.95T>C	p.Ile32Thr	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.95T>C	p.Ile32Thr	missense_variant	1/13	1	NM_178581.3	ENSP00000381237.3		Q8TCT9-2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000349

AC:

AN:

172056

Hom.:

AF XY:

0.0000428

AC XY:

AN XY:

93448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000378

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:

0.0000723

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000232

AC:

AN:

1421890

Hom.:

Cov.:

AF XY:

0.0000256

AC XY:

AN XY:

703706

show subpopulations

Gnomad4 AFR exome

AF:

0.0000305

Gnomad4 AMR exome

AF:

0.0000263

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:

0.0000284

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000338

AC:

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

Apr 26, 2023

The c.95T>C (p.I32T) alteration is located in exon 1 (coding exon 1) of the HM13 gene. This alteration results from a T to C substitution at nucleotide position 95, causing the isoleucine (I) at amino acid position 32 to be replaced by a threonine (T). 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

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.13

.;.;T;.;T;.

Eigen

Benign

0.012

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

D;D;D;D;.;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N;N;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.7

N;N;N;.;.;N

REVEL

Benign

0.12

Sift

Benign

0.19

T;T;T;.;.;T

Sift4G

Benign

0.62

T;T;T;.;T;T

Polyphen

0.73

P;P;P;.;.;.

Vest4

0.22

MutPred

0.48

Gain of glycosylation at I32 (P = 0.0056);Gain of glycosylation at I32 (P = 0.0056);Gain of glycosylation at I32 (P = 0.0056);Gain of glycosylation at I32 (P = 0.0056);Gain of glycosylation at I32 (P = 0.0056);Gain of glycosylation at I32 (P = 0.0056);

MVP

0.068

MPC

1.3

ClinPred

0.28

GERP RS

4.1

Varity_R

0.23

gMVP

0.41

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