4-83429553-A-G

Variant names:

• chr4-83429553-A-G
• NM_133636.5:c.2489T>C

Variant summary

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

The NM_133636.5(HELQ):​c.2489T>C​(p.Ile830Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000686 in 1,457,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

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 rank	MANE	Protein	UniProt
HELQ	NM_133636.5	c.2489T>C	p.Ile830Thr	missense_variant	Exon 12 of 18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.2288T>C	p.Ile763Thr	missense_variant	Exon 11 of 17		NP_001284684.2
HELQ	NM_001297756.2	c.998T>C	p.Ile333Thr	missense_variant	Exon 12 of 18		NP_001284685.1
HELQ	NM_001297757.2	c.857T>C	p.Ile286Thr	missense_variant	Exon 11 of 17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.2489T>C	p.Ile830Thr	missense_variant	Exon 12 of 18	1	NM_133636.5	ENSP00000295488.3
HELQ	ENST00000510985.1	c.2288T>C	p.Ile763Thr	missense_variant	Exon 11 of 17	1		ENSP00000424539.1
HELQ	ENST00000508591.5	n.*921T>C		non_coding_transcript_exon_variant	Exon 11 of 17	1		ENSP00000424186.1
HELQ	ENST00000508591.5	n.*921T>C		3_prime_UTR_variant	Exon 11 of 17	1		ENSP00000424186.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457154 Hom.: 0 Cov.: 29 AF XY: 0.00000690 AC XY: 5 AN XY: 725040

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: 0.00000901

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2489T>C (p.I830T) alteration is located in exon 12 (coding exon 12) of the HELQ gene. This alteration results from a T to C substitution at nucleotide position 2489, causing the isoleucine (I) at amino acid position 830 to be replaced by a threonine (T). 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	0.27
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;T
Sift4G	Uncertain	0.011	D;D
Polyphen		0.11	B;P
Vest4		0.72
MutPred		0.66		Gain of loop (P = 0.0195);.;
MVP		0.69
MPC		0.15
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84350706;