chr19-6664944-G-T

Variant names:

• chr19-6664944-G-T
• NM_001376887.1:c.705C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001376887.1(TNFSF14):​c.705C>A​(p.Phe235Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNFSF14 NM_001376887.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.80

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF14	NM_001376887.1	c.705C>A	p.Phe235Leu	missense_variant	Exon 4 of 4	ENST00000675206.1	NP_001363816.1
TNFSF14	NM_003807.5	c.705C>A	p.Phe235Leu	missense_variant	Exon 5 of 5		NP_003798.2
TNFSF14	NM_172014.3	c.597C>A	p.Phe199Leu	missense_variant	Exon 4 of 4		NP_742011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF14	ENST00000675206.1	c.705C>A	p.Phe235Leu	missense_variant	Exon 4 of 4		NM_001376887.1	ENSP00000502837.1
TNFSF14	ENST00000599359.1	c.705C>A	p.Phe235Leu	missense_variant	Exon 5 of 5	1		ENSP00000469049.1
TNFSF14	ENST00000245912.7	c.597C>A	p.Phe199Leu	missense_variant	Exon 4 of 4	1		ENSP00000245912.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	2.7
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.072	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.3	.;M
PrimateAI	Pathogenic	0.87	D
REVEL	Uncertain	0.45
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.91		.;Gain of MoRF binding (P = 0.0858);
MVP		0.96
MPC		1.2
ClinPred		0.92	D
GERP RS		-2.4
Varity_R		0.95
gMVP		0.89

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: chr19-6664955;