20-31514672-C-T

Position:

• chr20-31514672-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178581.3(HM13):​c.121C>T​(p.Leu41Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,406,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000014 (0 hom.)
• Consequence: HM13 NM_178581.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27498496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HM13	NM_178581.3	c.121C>T	p.Leu41Phe	missense_variant	1/13	ENST00000398174.9	NP_848696.1
HM13	NM_178580.3	c.121C>T	p.Leu41Phe	missense_variant	1/13		NP_848695.1
HM13	NM_030789.4	c.121C>T	p.Leu41Phe	missense_variant	1/12		NP_110416.1
HM13	NM_178582.3	c.121C>T	p.Leu41Phe	missense_variant	1/3		NP_848697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HM13	ENST00000398174.9	c.121C>T	p.Leu41Phe	missense_variant	1/13	1	NM_178581.3	ENSP00000381237.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1406750 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 694748

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: 9.22e-7

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The c.121C>T (p.L41F) 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 121, causing the leucine (L) at amino acid position 41 to be replaced by a phenylalanine (F). 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	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;.;T;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.84	T;T;T;D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.27	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.8	N;N;N;.;.;N
REVEL	Benign	0.038
Sift	Benign	0.043	D;T;T;.;.;T
Sift4G	Benign	0.26	T;T;T;.;T;T
Polyphen		0.72	P;B;D;.;.;.
Vest4		0.18
MutPred		0.41		Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);Gain of loop (P = 0.0121);
MVP		0.10
MPC		0.74
ClinPred		0.85	D
GERP RS		4.1
Varity_R		0.22
gMVP		0.57

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

Other links and lift over

dbSNP: rs1365316672; hg19: chr20-30102475;