chr4-83416818-G-C

Position:

• chr4-83416818-G-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.3111C>G​(p.His1037Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,408 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: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.503

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=0.22463837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELQ	NM_133636.5	c.3111C>G	p.His1037Gln	missense_variant	17/18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.2910C>G	p.His970Gln	missense_variant	16/17		NP_001284684.2
HELQ	NM_001297756.2	c.1620C>G	p.His540Gln	missense_variant	17/18		NP_001284685.1
HELQ	NM_001297757.2	c.1479C>G	p.His493Gln	missense_variant	16/17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.3111C>G	p.His1037Gln	missense_variant	17/18	1	NM_133636.5	ENSP00000295488	P1
HELQ	ENST00000510985.1	c.2910C>G	p.His970Gln	missense_variant	16/17	1		ENSP00000424539
HELQ	ENST00000508591.5	c.*1543C>G		3_prime_UTR_variant, NMD_transcript_variant	16/17	1		ENSP00000424186
HELQ	ENST00000512539.1	n.437+4745C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461408 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727036

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

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 21, 2024

The c.3111C>G (p.H1037Q) 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 3111, causing the histidine (H) at amino acid position 1037 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.091
Sift	Benign	0.14	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.044	B;P
Vest4		0.39
MutPred		0.34		Gain of MoRF binding (P = 0.089);.;
MVP		0.74
MPC		0.11
ClinPred		0.78	D
GERP RS		3.7
Varity_R		0.30
gMVP		0.38

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: rs981024095; hg19: chr4-84337971;