4-112278086-G-T

Position:

• chr4-112278086-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000361717.4(TIFA):​c.331C>A​(p.Leu111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIFA ENST00000361717.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

Genes affected

TIFA (HGNC:19075): (TRAF interacting protein with forkhead associated domain) This gene encodes an adapter protein involved in adaptive and innate immunity. This protein includes a forkhead-associated (FHA) domain that specifically binds to phosphorylated serine and threonine residues. In response to bacterial infection, the encoded host cell protein undergoes an intermolecular interaction between the FHA domain and a phosphorylated threonine that leads to protein oligomerization and stimulation of the NF-kappa B and other downstream signaling pathways. This protein exhibits reduced expression in hepatocellular carcinoma and may suppress hepatocellular carcinoma progression. This protein may also play a role in the DNA damage response. [provided by RefSeq, Jun 2018]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIFA	NM_052864.3	c.331C>A	p.Leu111Met	missense_variant	2/2	ENST00000361717.4	NP_443096.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIFA	ENST00000361717.4	c.331C>A	p.Leu111Met	missense_variant	2/2	1	NM_052864.3	ENSP00000354911.2
TIFA	ENST00000500655.2	c.331C>A	p.Leu111Met	missense_variant	2/2	3		ENSP00000424231.1
TIFA	ENST00000610220.2	c.331C>A	p.Leu111Met	missense_variant	2/2	6		ENSP00000516322.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Jun 22, 2023

The c.331C>A (p.L111M) alteration is located in exon 2 (coding exon 1) of the TIFA gene. This alteration results from a C to A substitution at nucleotide position 331, causing the leucine (L) at amino acid position 111 to be replaced by a methionine (M). 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	0.32
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.79		Loss of catalytic residue at L111 (P = 0.0957);Loss of catalytic residue at L111 (P = 0.0957);
MVP		0.89
MPC		1.1
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.47
gMVP		0.42

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: chr4-113199242;