4-83416862-G-C

Position:

• chr4-83416862-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_133636.5(HELQ):​c.3067C>G​(p.Arg1023Gly) variant causes a missense change. 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: HELQ NM_133636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.73

Genes affected

HELQ (HGNC:18536): (helicase, POLQ like) HEL308 is a single-stranded DNA-dependent ATPase and DNA helicase (Marini and Wood, 2002 [PubMed 11751861]).[supplied by OMIM, Mar 2008]

HELQ (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELQ	NM_133636.5	c.3067C>G	p.Arg1023Gly	missense_variant	17/18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.2866C>G	p.Arg956Gly	missense_variant	16/17		NP_001284684.2
HELQ	NM_001297756.2	c.1576C>G	p.Arg526Gly	missense_variant	17/18		NP_001284685.1
HELQ	NM_001297757.2	c.1435C>G	p.Arg479Gly	missense_variant	16/17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.3067C>G	p.Arg1023Gly	missense_variant	17/18	1	NM_133636.5	ENSP00000295488.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 13, 2024

The c.3067C>G (p.R1023G) alteration is located in exon 17 (coding exon 17) of the HELQ gene. This alteration results from a C to G substitution at nucleotide position 3067, causing the arginine (R) at amino acid position 1023 to be replaced by a glycine (G). 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	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	3.7	H;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.64		Loss of methylation at R1023 (P = 0.012);.;
MVP		0.91
MPC		0.60
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs750709425; hg19: chr4-84338015;