chr19-6665332-G-A

Position:

• chr19-6665332-G-A

Variant summary

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

The NM_001376887.1(TNFSF14):​c.317C>T​(p.Thr106Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,436,132 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TNFSF14 NM_001376887.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.263

Genes affected

TNFSF14 (HGNC:11930): (TNF superfamily member 14) The protein encoded by this gene is a member of the tumor necrosis factor (TNF) ligand family. This protein is a ligand for TNFRSF14, which is a member of the tumor necrosis factor receptor superfamily, and which is also known as a herpesvirus entry mediator (HVEM). This protein may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus. This protein has been shown to stimulate the proliferation of T cells, and trigger apoptosis of various tumor cells. This protein is also reported to prevent tumor necrosis factor alpha mediated apoptosis in primary hepatocyte. Two alternatively spliced transcript variant encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

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=0.041832447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFSF14	NM_001376887.1	c.317C>T	p.Thr106Ile	missense_variant	4/4	ENST00000675206.1	NP_001363816.1
TNFSF14	NM_003807.5	c.317C>T	p.Thr106Ile	missense_variant	5/5		NP_003798.2
TNFSF14	NM_172014.3	c.209C>T	p.Thr70Ile	missense_variant	4/4		NP_742011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF14	ENST00000675206.1	c.317C>T	p.Thr106Ile	missense_variant	4/4		NM_001376887.1	ENSP00000502837.1
TNFSF14	ENST00000599359.1	c.317C>T	p.Thr106Ile	missense_variant	5/5	1		ENSP00000469049.1
TNFSF14	ENST00000245912.7	c.209C>T	p.Thr70Ile	missense_variant	4/4	1		ENSP00000245912.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436132 Hom.: 0 Cov.: 36 AF XY: 0.00000281 AC XY: 2 AN XY: 712636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000244

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000841 AC: 1

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 15, 2021

The c.317C>T (p.T106I) alteration is located in exon 5 (coding exon 4) of the TNFSF14 gene. This alteration results from a C to T substitution at nucleotide position 317, causing the threonine (T) at amino acid position 106 to be replaced by an isoleucine (I). 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	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.6
DANN	Benign	0.93
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.024
Sift	Benign	0.20	T;.
Sift4G	Benign	0.36	T;T
Polyphen		0.0010	B;B
Vest4		0.039
MutPred		0.24		.;Loss of disorder (P = 0.0306);
MVP		0.20
MPC		0.37
ClinPred		0.24	T
GERP RS		-0.94
Varity_R		0.091
gMVP		0.39

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: rs757864251; hg19: chr19-6665343;