19-6664944-G-A

Position:

• chr19-6664944-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001376887.1(TNFSF14):​c.705C>T​(p.Phe235=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,597,244 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (16 hom.)
• Consequence: TNFSF14 NM_001376887.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 19-6664944-G-A is Benign according to our data. Variant chr19-6664944-G-A is described in ClinVar as [Benign]. Clinvar id is 777388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (853/152272) while in subpopulation AFR AF= 0.0167 (692/41560). AF 95% confidence interval is 0.0156. There are 10 homozygotes in gnomad4. There are 449 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFSF14	NM_001376887.1	c.705C>T	p.Phe235=	synonymous_variant	4/4	ENST00000675206.1	NP_001363816.1
TNFSF14	NM_003807.5	c.705C>T	p.Phe235=	synonymous_variant	5/5		NP_003798.2
TNFSF14	NM_172014.3	c.597C>T	p.Phe199=	synonymous_variant	4/4		NP_742011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF14	ENST00000675206.1	c.705C>T	p.Phe235=	synonymous_variant	4/4		NM_001376887.1	ENSP00000502837	P1
TNFSF14	ENST00000599359.1	c.705C>T	p.Phe235=	synonymous_variant	5/5	1		ENSP00000469049	P1
TNFSF14	ENST00000245912.7	c.597C>T	p.Phe199=	synonymous_variant	4/4	1		ENSP00000245912

Frequencies

GnomAD3 genomes AF: 0.00558 AC: 849 AN: 152154 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00244 AC: 600 AN: 246206 Hom.: 9 AF XY: 0.00214 AC XY: 284 AN XY: 132862

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.0150

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.000407

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00137 AC: 1980 AN: 1444972 Hom.: 16 Cov.: 29 AF XY: 0.00134 AC XY: 958 AN XY: 715480

Gnomad4 AFR exome AF: 0.0185

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000282

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000552

Gnomad4 OTH exome AF: 0.00342

GnomAD4 genome AF: 0.00560 AC: 853 AN: 152272 Hom.: 10 Cov.: 31 AF XY: 0.00603 AC XY: 449 AN XY: 74452

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00423 Hom.: 0

Bravo AF: 0.00669

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.2
DANN	Benign	0.60

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: rs79452416; hg19: chr19-6664955;