4-83427715-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133636.5(HELQ):c.2524A>G(p.Ile842Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000362 in 1,381,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.07

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17872462).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HELQ	NM_133636.5	c.2524A>G	p.Ile842Val	missense_variant	13/18	ENST00000295488.8
HELQ	NM_001297755.2	c.2323A>G	p.Ile775Val	missense_variant	12/17
HELQ	NM_001297756.2	c.1033A>G	p.Ile345Val	missense_variant	13/18
HELQ	NM_001297757.2	c.892A>G	p.Ile298Val	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HELQ	ENST00000295488.8	c.2524A>G	p.Ile842Val	missense_variant	13/18	1	NM_133636.5	P1
HELQ	ENST00000510985.1	c.2323A>G	p.Ile775Val	missense_variant	12/17	1
HELQ	ENST00000508591.5	c.*956A>G		3_prime_UTR_variant, NMD_transcript_variant	12/17	1
HELQ	ENST00000512539.1	n.12A>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000103 AC: 2 AN: 193522 Hom.: 0 AF XY: 0.00000946 AC XY: 1 AN XY: 105746

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1381226 Hom.: 0 Cov.: 27 AF XY: 0.00000438 AC XY: 3 AN XY: 684626

Gnomad4 AFR exome AF: 0.000135

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.32e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Feb 28, 2024

The c.2524A>G (p.I842V) alteration is located in exon 13 (coding exon 13) of the HELQ gene. This alteration results from a A to G substitution at nucleotide position 2524, causing the isoleucine (I) at amino acid position 842 to be replaced by a valine (V). 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	Benign	0.061
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0030	T;T
Eigen	Benign	-0.034
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.10
Sift	Benign	0.23	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.038	B;B
Vest4		0.20
MutPred		0.42		Loss of helix (P = 0.0196);.;
MVP		0.71
MPC		0.093
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.057
gMVP		0.17

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: rs776776755; hg19: chr4-84348868;