3-156704932-T-C

Position:

• chr3-156704932-T-C

Variant summary

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

The NM_015508.5(TIPARP):​c.1775T>C​(p.Leu592Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIPARP NM_015508.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

TIPARP (HGNC:23696): (TCDD inducible poly(ADP-ribose) polymerase) This gene encodes a member of the poly(ADP-ribose) polymerase superfamily. Studies of the mouse ortholog have shown that the encoded protein catalyzes histone poly(ADP-ribosyl)ation and may be involved in T-cell function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIPARP	NM_015508.5	c.1775T>C	p.Leu592Pro	missense_variant	6/6	ENST00000295924.12
TIPARP	NM_001184717.1	c.1775T>C	p.Leu592Pro	missense_variant	6/6
TIPARP	NM_001184718.2	c.1775T>C	p.Leu592Pro	missense_variant	6/6
TIPARP	XM_047447935.1	c.1775T>C	p.Leu592Pro	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIPARP	ENST00000295924.12	c.1775T>C	p.Leu592Pro	missense_variant	6/6	1	NM_015508.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Dec 12, 2023

The c.1775T>C (p.L592P) alteration is located in exon 6 (coding exon 5) of the TIPARP gene. This alteration results from a T to C substitution at nucleotide position 1775, causing the leucine (L) at amino acid position 592 to be replaced by a proline (P). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T;T;.;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	.;.;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.8	H;H;H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.4	D;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.98
MutPred		0.88		Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);Gain of disorder (P = 0.0078);
MVP		0.82
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.98

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: chr3-156422721;