11-113689859-A-C

Variant names:

• chr11-113689859-A-C
• rs2134780588
• NM_030770.4:c.1265T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_030770.4(TMPRSS5):​c.1265T>G​(p.Val422Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

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.1265T>G	p.Val422Gly	missense	Exon 12 of 13	NP_110397.2	Q9H3S3
	TMPRSS5	NM_001288751.2		c.1238T>G	p.Val413Gly	missense	Exon 12 of 13	NP_001275680.1	F5GX83
	TMPRSS5	NM_001288750.2		c.1133T>G	p.Val378Gly	missense	Exon 11 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.1265T>G	p.Val422Gly	missense	Exon 12 of 13	ENSP00000299882.5	Q9H3S3
	TMPRSS5	ENST00000545579.6	TSL:1	c.1238T>G	p.Val413Gly	missense	Exon 12 of 13	ENSP00000441104.1	F5GX83
	TMPRSS5	ENST00000538955.5	TSL:1	c.1133T>G	p.Val378Gly	missense	Exon 11 of 12	ENSP00000445528.1	F5H2M3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	0.68
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.77
Sift	Benign	0.095	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.0070	B
Vest4		0.67
MutPred		0.77		Loss of stability (P = 0.0204)
MVP		0.88
MPC		0.10
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.63
gMVP		0.96
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2134780588; hg19: chr11-113560581;