15-72258102-T-C

Position:

• chr15-72258102-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001323532.2(PARP6):​c.841A>G​(p.Thr281Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PARP6 NM_001323532.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

PARP6 (HGNC:26921): (poly(ADP-ribose) polymerase family member 6) Enables protein ADP-ribosylase activity. Involved in protein auto-ADP-ribosylation and protein mono-ADP-ribosylation. [provided by Alliance of Genome Resources, Apr 2022]

PARP6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36392725).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP6	NM_001323532.2	c.841A>G	p.Thr281Ala	missense_variant	12/24	ENST00000569795.6	NP_001310461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP6	ENST00000569795.6	c.841A>G	p.Thr281Ala	missense_variant	12/24	5	NM_001323532.2	ENSP00000456348.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461454 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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 05, 2022

The c.841A>G (p.T281A) alteration is located in exon 11 (coding exon 10) of the PARP6 gene. This alteration results from a A to G substitution at nucleotide position 841, causing the threonine (T) at amino acid position 281 to be replaced by an alanine (A). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.8	L;.;L;L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.0	N;.;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.039	D;.;D;D;T
Sift4G	Benign	0.084	T;T;T;T;T
Polyphen		0.98	D;.;.;D;.
Vest4		0.52
MutPred		0.38		Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);Gain of helix (P = 0.0225);
MVP		0.20
MPC		1.1
ClinPred		0.79	D
GERP RS		5.0
Varity_R		0.17
gMVP		0.43

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: chr15-72550443; COSMIC: COSV53002356; COSMIC: COSV53002356;