chr1-2559867-G-C

Variant names:

• chr1-2559867-G-C
• rs2234163
• NM_003820.4:c.349G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000355716.5(TNFRSF14):​c.349G>C​(p.Ala117Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A117T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF14 ENST00000355716.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

Genes affected

TNFRSF14 (HGNC:11912): (TNF receptor superfamily member 14) This gene encodes a member of the TNF (tumor necrosis factor) receptor superfamily. The encoded protein functions in signal transduction pathways that activate inflammatory and inhibitory T-cell immune response. It binds herpes simplex virus (HSV) viral envelope glycoprotein D (gD), mediating its entry into cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355716.5. 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
	TNFRSF14	NM_003820.4	MANE Select	c.349G>C	p.Ala117Pro	missense	Exon 4 of 8	NP_003811.2
	TNFRSF14	NM_001297605.2		c.349G>C	p.Ala117Pro	missense	Exon 4 of 7	NP_001284534.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF14	ENST00000355716.5	TSL:1 MANE Select	c.349G>C	p.Ala117Pro	missense	Exon 4 of 8	ENSP00000347948.4
	TNFRSF14	ENST00000475523.5	TSL:1	n.586G>C		non_coding_transcript_exon	Exon 2 of 6
	TNFRSF14	ENST00000434817.5	TSL:3	c.349G>C	p.Ala117Pro	missense	Exon 5 of 7	ENSP00000415254.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.065	N
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	1.2	L
PhyloP100		-1.2
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.094	T
Polyphen		1.0	D
Vest4		0.20
MutPred		0.78		Gain of disorder (P = 0.0432)
MVP		0.61
MPC		0.61
ClinPred		0.34	T
GERP RS		0.45
Varity_R		0.74
gMVP		0.85
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2234163; hg19: chr1-2491306;