13-113424304-G-T

Position:

• chr13-113424304-G-T

Variant summary

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

The NM_001394807.1(ADPRHL1):​c.820C>A​(p.His274Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADPRHL1 NM_001394807.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.83

Genes affected

ADPRHL1 (HGNC:21303): (ADP-ribosylhydrolase like 1) ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases (see ART1; MIM 601625) transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL1, reverse the reaction (Glowacki et al., 2002 [PubMed 12070318]).[supplied by OMIM, Mar 2008]

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, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADPRHL1	NM_001394807.1	c.820C>A	p.His274Asn	missense_variant	6/8	ENST00000612156.3	NP_001381736.1
ADPRHL1	NM_138430.5	c.820C>A	p.His274Asn	missense_variant	6/7		NP_612439.2
ADPRHL1	NM_199162.3	c.574C>A	p.His192Asn	missense_variant	6/7		NP_954631.1
ADPRHL1	XM_047430086.1	c.574C>A	p.His192Asn	missense_variant	6/8		XP_047286042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADPRHL1	ENST00000612156.3	c.820C>A	p.His274Asn	missense_variant	6/8	5	NM_001394807.1	ENSP00000489048.1
ADPRHL1	ENST00000375418.8	c.820C>A	p.His274Asn	missense_variant	6/7	1		ENSP00000364567.3
ADPRHL1	ENST00000356501.8	c.574C>A	p.His192Asn	missense_variant	6/7	1		ENSP00000348894.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 17, 2022

The c.820C>A (p.H274N) alteration is located in exon 6 (coding exon 6) of the ADPRHL1 gene. This alteration results from a C to A substitution at nucleotide position 820, causing the histidine (H) at amino acid position 274 to be replaced by an asparagine (N). 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	0.87
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T;.;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.4	.;.;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.0	.;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0090	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.67
MutPred		0.88		Gain of MoRF binding (P = 0.0999);.;Gain of MoRF binding (P = 0.0999);
MVP		0.43
MPC		0.44
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.60
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779414316; hg19: chr13-114078619;