11-117903767-C-T

Variant names:

• chr11-117903767-C-T
• rs768532711
• NM_001077263.3:c.1565G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001077263.3(TMPRSS13):​c.1565G>A​(p.Arg522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,612,074 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.000025 (1 hom.)
• Consequence: TMPRSS13 NM_001077263.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.480

Genes affected

TMPRSS13 (HGNC:29808): (transmembrane serine protease 13) This gene encodes a member of the type II transmembrane serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Transmembrane serine proteases are regulated by protease inhibitors and known to function in development, homeostasis, infection, and tumorigenesis. This protein facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. [provided by RefSeq, Aug 2021]

ACMG classification

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=0.164538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS13	NM_001077263.3	c.1565G>A	p.Arg522His	missense_variant	Exon 12 of 13	ENST00000524993.6	NP_001070731.1
TMPRSS13	NM_001244995.2	c.1565G>A	p.Arg522His	missense_variant	Exon 12 of 13		NP_001231924.1
TMPRSS13	NM_001206789.2	c.1460G>A	p.Arg487His	missense_variant	Exon 11 of 12		NP_001193718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS13	ENST00000524993.6	c.1565G>A	p.Arg522His	missense_variant	Exon 12 of 13	1	NM_001077263.3	ENSP00000434279.1
TMPRSS13	ENST00000445164.6	c.1565G>A	p.Arg522His	missense_variant	Exon 12 of 12	1		ENSP00000394114.2
TMPRSS13	ENST00000430170.6	c.1565G>A	p.Arg522His	missense_variant	Exon 12 of 13	1		ENSP00000387702.2
TMPRSS13	ENST00000528626.5	c.1460G>A	p.Arg487His	missense_variant	Exon 11 of 12	1		ENSP00000435813.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000368 AC: 9 AN: 244700 Hom.: 0 AF XY: 0.0000452 AC XY: 6 AN XY: 132800

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.000100

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1459852 Hom.: 1 Cov.: 36 AF XY: 0.0000303 AC XY: 22 AN XY: 726040

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000901

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1565G>A (p.R522H) alteration is located in exon 12 (coding exon 12) of the TMPRSS13 gene. This alteration results from a G to A substitution at nucleotide position 1565, causing the arginine (R) at amino acid position 522 to be replaced by a histidine (H). 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	0.069
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	.;T;.;T
Eigen	Benign	-0.0039
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.8	.;.;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.017	D;D;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.95	.;P;.;.
Vest4		0.21
MVP		0.78
MPC		0.32
ClinPred		0.043	T
GERP RS		3.2
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs768532711; hg19: chr11-117774482;