4-67919106-A-C

Position:

• chr4-67919106-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001114387.2(TMPRSS11A):​c.819T>G​(p.Ile273Met) variant causes a missense change involving the alteration of a non-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: TMPRSS11A NM_001114387.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.826

Genes affected

TMPRSS11A (HGNC:27954): (transmembrane serine protease 11A) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be located in extracellular region. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS11A	NM_001114387.2	c.819T>G	p.Ile273Met	missense_variant	8/10	ENST00000508048.6	NP_001107859.1
TMPRSS11A	NM_182606.4	c.828T>G	p.Ile276Met	missense_variant	8/10		NP_872412.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11A	ENST00000508048.6	c.819T>G	p.Ile273Met	missense_variant	8/10	1	NM_001114387.2	ENSP00000426911	P3
UBA6-DT	ENST00000500538.7	n.1988-143501A>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Nov 06, 2023

The c.828T>G (p.I276M) alteration is located in exon 8 (coding exon 8) of the TMPRSS11A gene. This alteration results from a T to G substitution at nucleotide position 828, causing the isoleucine (I) at amino acid position 276 to be replaced by a methionine (M). 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	0.34
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	16
DANN	Uncertain	1.0
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.0020
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.72	.;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.0020	D;D;D
Vest4		0.73
MutPred		0.86		.;Gain of MoRF binding (P = 0.0774);.;
MVP		0.86
MPC		0.49
ClinPred		0.98	D
GERP RS		1.1
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-68784824;