4-68476288-T-C

Variant names:

• chr4-68476288-T-C
• rs1312933392
• NM_014058.4:c.557T>C

Variant summary

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

The NM_014058.4(TMPRSS11E):​c.557T>C​(p.Leu186Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS11E NM_014058.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.544

Genes affected

TMPRSS11E (HGNC:24465): (transmembrane serine protease 11E) Predicted to enable serine-type peptidase activity. Involved in cognition. Predicted to be integral component of plasma membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
TMPRSS11E	NM_014058.4	c.557T>C	p.Leu186Pro	missense_variant	Exon 7 of 10	ENST00000305363.9	NP_054777.2
TMPRSS11E	XM_011531896.3	c.323T>C	p.Leu108Pro	missense_variant	Exon 6 of 9		XP_011530198.1
TMPRSS11E	XM_047450139.1	c.323T>C	p.Leu108Pro	missense_variant	Exon 7 of 10		XP_047306095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS11E	ENST00000305363.9	c.557T>C	p.Leu186Pro	missense_variant	Exon 7 of 10	1	NM_014058.4	ENSP00000307519.4
TMPRSS11E	ENST00000510647.1	n.*6T>C		non_coding_transcript_exon_variant	Exon 5 of 6	3		ENSP00000424109.1
TMPRSS11E	ENST00000510647.1	n.*6T>C		3_prime_UTR_variant	Exon 5 of 6	3		ENSP00000424109.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248728 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

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.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.557T>C (p.L186P) alteration is located in exon 7 (coding exon 7) of the TMPRSS11E gene. This alteration results from a T to C substitution at nucleotide position 557, causing the leucine (L) at amino acid position 186 to be replaced by a proline (P). 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	0.053
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.45
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00097	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.17
Sift	Benign	0.21	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.076
MutPred		0.47		Loss of stability (P = 0.0088);
MVP		0.61
MPC		0.17
ClinPred		0.051	T
GERP RS		1.7
Varity_R		0.045
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1312933392; hg19: chr4-69342006;