19-6665009-T-C

Variant names:

• chr19-6665009-T-C
• rs344560
• NM_001376887.1:c.640A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001376887.1(TNFSF14):​c.640A>G​(p.Lys214Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.946 in 1,613,832 control chromosomes in the GnomAD database, including 722,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.95 (69180 hom., cov: 32)
  • Exomes 𝑓: 0.95 (653256 hom.)
• Consequence: TNFSF14 NM_001376887.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0570
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.5369017E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376887.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF14	NM_001376887.1	MANE Select	c.640A>G	p.Lys214Glu	missense	Exon 4 of 4	NP_001363816.1
	TNFSF14	NM_003807.5		c.640A>G	p.Lys214Glu	missense	Exon 5 of 5	NP_003798.2
	TNFSF14	NM_172014.3		c.532A>G	p.Lys178Glu	missense	Exon 4 of 4	NP_742011.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF14	ENST00000675206.1	MANE Select	c.640A>G	p.Lys214Glu	missense	Exon 4 of 4	ENSP00000502837.1
	TNFSF14	ENST00000599359.1	TSL:1	c.640A>G	p.Lys214Glu	missense	Exon 5 of 5	ENSP00000469049.1
	TNFSF14	ENST00000245912.7	TSL:1	c.532A>G	p.Lys178Glu	missense	Exon 4 of 4	ENSP00000245912.3

Frequencies

GnomAD3 genomes AF: 0.953 AC: 145000 AN: 152194 Hom.: 69124 Cov.: 32

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.933

Gnomad ASJ AF: 0.907

Gnomad EAS AF: 0.928

Gnomad SAS AF: 0.965

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.944

Gnomad OTH AF: 0.947

GnomAD2 exomes AF: 0.947 AC: 237897 AN: 251330 AF XY: 0.947

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.946

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 0.922

Gnomad FIN exome AF: 0.942

Gnomad NFE exome AF: 0.945

Gnomad OTH exome AF: 0.941

GnomAD4 exome AF: 0.945 AC: 1381778 AN: 1461520 Hom.: 653256 Cov.: 78 AF XY: 0.946 AC XY: 687629 AN XY: 726972

African (AFR) AF: 0.988 AC: 33072 AN: 33474

American (AMR) AF: 0.946 AC: 42313 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 23704 AN: 26132

East Asian (EAS) AF: 0.934 AC: 37065 AN: 39682

South Asian (SAS) AF: 0.963 AC: 83074 AN: 86252

European-Finnish (FIN) AF: 0.942 AC: 50315 AN: 53406

Middle Eastern (MID) AF: 0.957 AC: 5516 AN: 5766

European-Non Finnish (NFE) AF: 0.944 AC: 1049747 AN: 1111716

Other (OTH) AF: 0.944 AC: 56972 AN: 60374

GnomAD4 genome AF: 0.953 AC: 145115 AN: 152312 Hom.: 69180 Cov.: 32 AF XY: 0.953 AC XY: 70986 AN XY: 74486

African (AFR) AF: 0.986 AC: 40967 AN: 41566

American (AMR) AF: 0.933 AC: 14277 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.907 AC: 3150 AN: 3472

East Asian (EAS) AF: 0.928 AC: 4798 AN: 5172

South Asian (SAS) AF: 0.965 AC: 4657 AN: 4826

European-Finnish (FIN) AF: 0.946 AC: 10051 AN: 10622

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.944 AC: 64220 AN: 68030

Other (OTH) AF: 0.947 AC: 2000 AN: 2112

Alfa AF: 0.945 Hom.: 319514

Bravo AF: 0.952

TwinsUK AF: 0.943 AC: 3498

ALSPAC AF: 0.944 AC: 3640

ESP6500AA AF: 0.984 AC: 4336

ESP6500EA AF: 0.945 AC: 8126

ExAC AF: 0.948 AC: 115148

Asia WGS AF: 0.958 AC: 3332 AN: 3478

EpiCase AF: 0.943

EpiControl AF: 0.944

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Benign	0.30
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0000035	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.88	N
PhyloP100		0.057
PrimateAI	Uncertain	0.56	T
REVEL	Benign	0.28
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.082
MPC		0.46
ClinPred		0.0022	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs344560; hg19: chr19-6665020; COSMIC: COSV55591361;