4-68072346-T-C

Position:

• chr4-68072346-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207407.2(TMPRSS11F):​c.491A>G​(p.Asn164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TMPRSS11F NM_207407.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.324

Genes affected

TMPRSS11F (HGNC:29994): (transmembrane serine protease 11F) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within regulation of water loss via skin. Located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

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

LOC550113 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034389406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS11F	NM_207407.2	c.491A>G	p.Asn164Ser	missense_variant	5/10	ENST00000356291.3	NP_997290.2
LOC550113	NR_046116.1	n.2659-759T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11F	ENST00000356291.3	c.491A>G	p.Asn164Ser	missense_variant	5/10	2	NM_207407.2	ENSP00000348639	P1
UBA6-DT	ENST00000500538.7	n.2603-7775T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444404 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718384

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

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

Feb 13, 2024

The c.491A>G (p.N164S) alteration is located in exon 5 (coding exon 5) of the TMPRSS11F gene. This alteration results from a A to G substitution at nucleotide position 491, causing the asparagine (N) at amino acid position 164 to be replaced by a serine (S). 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	0.062
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.83
DANN	Benign	0.83
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.071
Sift	Benign	0.20	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.47		Loss of catalytic residue at N164 (P = 0.0076);
MVP		0.11
MPC		0.055
ClinPred		0.033	T
GERP RS		-2.2
Varity_R		0.067
gMVP		0.15

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: rs1560396766; hg19: chr4-68938064;