11-113690262-C-T

Variant names:

• chr11-113690262-C-T
• rs528227924
• NM_030770.4:c.1175G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_030770.4(TMPRSS5):​c.1175G>A​(p.Gly392Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,404,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G392V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.94
• Publications: 0 publications found

Genes affected

TMPRSS5 (HGNC:14908): (transmembrane serine protease 5) This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS5 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030770.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS5	NM_030770.4	MANE Select	c.1175G>A	p.Gly392Asp	missense	Exon 11 of 13	NP_110397.2	Q9H3S3
	TMPRSS5	NM_001288751.2		c.1148G>A	p.Gly383Asp	missense	Exon 11 of 13	NP_001275680.1	F5GX83
	TMPRSS5	NM_001288750.2		c.1043G>A	p.Gly348Asp	missense	Exon 10 of 12	NP_001275679.1	F5H2M3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS5	ENST00000299882.11	TSL:1 MANE Select	c.1175G>A	p.Gly392Asp	missense	Exon 11 of 13	ENSP00000299882.5	Q9H3S3
	TMPRSS5	ENST00000545579.6	TSL:1	c.1148G>A	p.Gly383Asp	missense	Exon 11 of 13	ENSP00000441104.1	F5GX83
	TMPRSS5	ENST00000538955.5	TSL:1	c.1043G>A	p.Gly348Asp	missense	Exon 10 of 12	ENSP00000445528.1	F5H2M3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000600 AC: 1 AN: 166802 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404142 Hom.: 0 Cov.: 51 AF XY: 0.00 AC XY: 0 AN XY: 693218

African (AFR) AF: 0.00 AC: 0 AN: 31712

American (AMR) AF: 0.00 AC: 0 AN: 36026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 35920

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082486

Other (OTH) AF: 0.00 AC: 0 AN: 58276

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.74
Sift	Benign	0.032	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.96		Loss of methylation at R397 (P = 0.0954)
MVP		0.95
MPC		0.43
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.91
gMVP		0.94
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs528227924; hg19: chr11-113560984;