4-67919168-T-C

Position:

• chr4-67919168-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001114387.2(TMPRSS11A):​c.757A>G​(p.Arg253Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,854 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: 0.0000027 (0 hom.)
• Consequence: TMPRSS11A NM_001114387.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS11A	NM_001114387.2	c.757A>G	p.Arg253Gly	missense_variant	8/10	ENST00000508048.6	NP_001107859.1
TMPRSS11A	NM_182606.4	c.766A>G	p.Arg256Gly	missense_variant	8/10		NP_872412.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11A	ENST00000508048.6	c.757A>G	p.Arg253Gly	missense_variant	8/10	1	NM_001114387.2	ENSP00000426911	P3
UBA6-DT	ENST00000500538.7	n.1988-143439T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

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: 0.00000360

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.766A>G (p.R256G) alteration is located in exon 8 (coding exon 8) of the TMPRSS11A gene. This alteration results from a A to G substitution at nucleotide position 766, causing the arginine (R) at amino acid position 256 to be replaced by a glycine (G). 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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.5	.;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.012	D;D;D
Vest4		0.74
MutPred		0.68		.;Loss of MoRF binding (P = 0.0315);.;
MVP		0.93
MPC		0.57
ClinPred		1.0	D
GERP RS		4.2
gMVP		0.95

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: chr4-68784886;