4-83427619-T-C

Variant summary

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

The NM_133636.5(HELQ):c.2620A>G(p.Thr874Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 8.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HELQ	NM_133636.5	c.2620A>G	p.Thr874Ala	missense_variant	13/18	ENST00000295488.8
HELQ	NM_001297755.2	c.2419A>G	p.Thr807Ala	missense_variant	12/17
HELQ	NM_001297756.2	c.1129A>G	p.Thr377Ala	missense_variant	13/18
HELQ	NM_001297757.2	c.988A>G	p.Thr330Ala	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HELQ	ENST00000295488.8	c.2620A>G	p.Thr874Ala	missense_variant	13/18	1	NM_133636.5	P1
HELQ	ENST00000510985.1	c.2419A>G	p.Thr807Ala	missense_variant	12/17	1
HELQ	ENST00000508591.5	c.*1052A>G		3_prime_UTR_variant, NMD_transcript_variant	12/17	1
HELQ	ENST00000512539.1	n.108A>G		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000820 AC: 2 AN: 243936 Hom.: 0 AF XY: 0.00000757 AC XY: 1 AN XY: 132114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000568

Gnomad SAS exome AF: 0.0000340

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Mar 01, 2023

The c.2620A>G (p.T874A) 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 2620, causing the threonine (T) at amino acid position 874 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	Benign	0.17
BayesDel_addAF	Benign	-0.0039	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.095	T;T
Sift4G	Benign	0.087	T;T
Polyphen		0.85	P;D
Vest4		0.73
MutPred		0.52		Loss of glycosylation at T874 (P = 0.0931);.;
MVP		0.86
MPC		0.34
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.24
gMVP		0.78

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: rs745569615; hg19: chr4-84348772;