4-67911349-C-T

Variant names:

• chr4-67911349-C-T
• rs1004143120
• NM_001114387.2:c.1250G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001114387.2(TMPRSS11A):​c.1250G>A​(p.Gly417Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,528 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS11A NM_001114387.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS11A	NM_001114387.2	c.1250G>A	p.Gly417Asp	missense_variant	Exon 10 of 10	ENST00000508048.6	NP_001107859.1
TMPRSS11A	NM_182606.4	c.1259G>A	p.Gly420Asp	missense_variant	Exon 10 of 10		NP_872412.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS11A	ENST00000508048.6	c.1250G>A	p.Gly417Asp	missense_variant	Exon 10 of 10	1	NM_001114387.2	ENSP00000426911.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460528 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1259G>A (p.G420D) alteration is located in exon 10 (coding exon 10) of the TMPRSS11A gene. This alteration results from a G to A substitution at nucleotide position 1259, causing the glycine (G) at amino acid position 420 to be replaced by an aspartic acid (D). 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	0.21
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	.;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	0.79	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.0	.;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.038	.;D;D
Sift4G	Uncertain	0.055	T;T;D
Vest4		0.48
MutPred		0.38		.;Loss of MoRF binding (P = 0.0195);.;
MVP		0.87
MPC		0.58
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs1004143120; hg19: chr4-68777067;