NM_030770.4:c.1175G>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_030770.4(TMPRSS5):​c.1175G>T​(p.Gly392Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000277 in 1,554,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• BS2: High AC in GnomAd4 at 23 AD gene.

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>T	p.Gly392Val	missense	Exon 11 of 13	NP_110397.2	Q9H3S3
	TMPRSS5	NM_001288751.2		c.1148G>T	p.Gly383Val	missense	Exon 11 of 13	NP_001275680.1	F5GX83
	TMPRSS5	NM_001288750.2		c.1043G>T	p.Gly348Val	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>T	p.Gly392Val	missense	Exon 11 of 13	ENSP00000299882.5	Q9H3S3
	TMPRSS5	ENST00000545579.6	TSL:1	c.1148G>T	p.Gly383Val	missense	Exon 11 of 13	ENSP00000441104.1	F5GX83
	TMPRSS5	ENST00000538955.5	TSL:1	c.1043G>T	p.Gly348Val	missense	Exon 10 of 12	ENSP00000445528.1	F5H2M3

Frequencies

GnomAD3 genomes AF: 0.000153 AC: 23 AN: 150652 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000561

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000420 AC: 7 AN: 166802 AF XY: 0.0000338

Gnomad AFR exome AF: 0.000822

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: 0.0000142 AC: 20 AN: 1404140 Hom.: 0 Cov.: 51 AF XY: 0.00000866 AC XY: 6 AN XY: 693216

African (AFR) AF: 0.000631 AC: 20 AN: 31710

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: 0.00 AC: 0 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 AF: 0.000153 AC: 23 AN: 150762 Hom.: 0 Cov.: 28 AF XY: 0.000122 AC XY: 9 AN XY: 73580

African (AFR) AF: 0.000559 AC: 23 AN: 41120

American (AMR) AF: 0.00 AC: 0 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 4988

South Asian (SAS) AF: 0.00 AC: 0 AN: 4718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67748

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.00000864 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.95
MPC		0.46
ClinPred		0.91	D
GERP RS		4.2
Varity_R		0.94
gMVP		0.91
Mutation Taster		=21/79	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;