4-68232414-T-C

Position:

• chr4-68232414-T-C

Variant summary

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

The NM_182502.3(TMPRSS11B):​c.472A>G​(p.Ile158Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS11B NM_182502.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

Genes affected

TMPRSS11B (HGNC:25398): (transmembrane serine protease 11B) Enables serine-type peptidase activity. Predicted to be involved in proteolysis. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMPRSS11B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS11B	NM_182502.3	c.472A>G	p.Ile158Val	missense_variant, splice_region_variant	6/10	ENST00000332644.6	NP_872308.2
TMPRSS11B	XM_011531608.3	c.472A>G	p.Ile158Val	missense_variant, splice_region_variant	6/11		XP_011529910.1
TMPRSS11B	XM_011531609.1	c.472A>G	p.Ile158Val	missense_variant, splice_region_variant	6/8		XP_011529911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11B	ENST00000332644.6	c.472A>G	p.Ile158Val	missense_variant, splice_region_variant	6/10	1	NM_182502.3	ENSP00000330475.5
TMPRSS11B	ENST00000502365.1	n.605A>G		splice_region_variant, non_coding_transcript_exon_variant	6/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Apr 22, 2022

The c.472A>G (p.I158V) alteration is located in exon 6 (coding exon 6) of the TMPRSS11B gene. This alteration results from a A to G substitution at nucleotide position 472, causing the isoleucine (I) at amino acid position 158 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.047
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.051	B
Vest4		0.19
MutPred		0.29		Gain of ubiquitination at K154 (P = 0.1317);
MVP		0.076
MPC		0.040
ClinPred		0.45	T
GERP RS		4.5
Varity_R		0.066
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-69098132;