Genetic Variant PARP14:p.Asp97His (chr3-122685286-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017554.3(PARP14):c.289G>C(p.Asp97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. D97N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PARP14
NM_017554.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.11

Publications

0 publications found

Variant links:

Genes affected

PARP14 (HGNC:29232): (poly(ADP-ribose) polymerase family member 14) This gene encodes a member of the poly(ADP-ribose) polymerase (PARP) protein family. The encoded anti-apoptotic protein may regulate aerobic glycolysis and promote survival of cancer cells. Increased expression of this gene has been reported in a variety of tumor types. [provided by RefSeq, Jul 2016]

PARP14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04481885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP14	NM_017554.3 link	c.289G>C	p.Asp97His	missense_variant	Exon 2 of 17	ENST00000474629.7	NP_060024.2	Q460N5-6Q8N546
PARP14	XM_011512929.3 link	c.289G>C	p.Asp97His	missense_variant	Exon 2 of 10		XP_011511231.1
PARP14	XR_007095695.1 link	n.334G>C		non_coding_transcript_exon_variant	Exon 2 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PARP14	ENST00000474629.7 link	c.289G>C	p.Asp97His	missense_variant	Exon 2 of 17	1	NM_017554.3	ENSP00000418194.2	Q460N5-6
PARP14	ENST00000494811.2 link	c.289G>C	p.Asp97His	missense_variant	Exon 2 of 4	4		ENSP00000418535.2	H7C4Y3
PARP14	ENST00000649945.1 link	n.289G>C		non_coding_transcript_exon_variant	Exon 2 of 16			ENSP00000497854.1	A0A3B3ITD5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727050

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111794

Other (OTH)

AF:

0.00

AC:

AN:

60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.8

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.0026

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.24

T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.2

N;.

PhyloP100

-1.1

PrimateAI

Benign

0.26

PROVEAN

Benign

0.90

N;.

REVEL

Benign

0.059

Sift

Benign

0.59

T;.

Sift4G

Benign

0.094

T;.

Polyphen

0.0010

B;.

Vest4

0.076

MutPred

0.16

Loss of stability (P = 0.1196);Loss of stability (P = 0.1196);

MVP

0.36

MPC

0.23

ClinPred

0.022

GERP RS

3.0

Varity_R

0.024

gMVP

0.29

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over