chr4-83448938-A-C

Variant names:

• chr4-83448938-A-C
• NM_133636.5:c.1036T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_133636.5(HELQ):​c.1036T>G​(p.Leu346Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELQ	NM_133636.5	c.1036T>G	p.Leu346Val	missense_variant	Exon 3 of 18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.1036T>G	p.Leu346Val	missense_variant	Exon 3 of 17		NP_001284684.2
HELQ	NM_001297756.2	c.-469T>G		5_prime_UTR_variant	Exon 3 of 18		NP_001284685.1
HELQ	NM_001297757.2	c.-499T>G		5_prime_UTR_variant	Exon 3 of 17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.1036T>G	p.Leu346Val	missense_variant	Exon 3 of 18	1	NM_133636.5	ENSP00000295488.3
HELQ	ENST00000510985.1	c.1036T>G	p.Leu346Val	missense_variant	Exon 3 of 17	1		ENSP00000424539.1
HELQ	ENST00000508591.5	n.1036T>G		non_coding_transcript_exon_variant	Exon 3 of 17	1		ENSP00000424186.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452994 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722718

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.97	D;D
Vest4		0.73
MutPred		0.78		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.49
MPC		0.45
ClinPred		0.99	D
GERP RS		-6.4
Varity_R		0.44
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-84370091;