4-83448938-A-T

Position:

• chr4-83448938-A-T

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>A​(p.Leu346Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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, 0.951

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELQ	NM_133636.5	c.1036T>A	p.Leu346Met	missense_variant	3/18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.1036T>A	p.Leu346Met	missense_variant	3/17		NP_001284684.2
HELQ	NM_001297756.2	c.-469T>A		5_prime_UTR_variant	3/18		NP_001284685.1
HELQ	NM_001297757.2	c.-499T>A		5_prime_UTR_variant	3/17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.1036T>A	p.Leu346Met	missense_variant	3/18	1	NM_133636.5	ENSP00000295488	P1
HELQ	ENST00000510985.1	c.1036T>A	p.Leu346Met	missense_variant	3/17	1		ENSP00000424539
HELQ	ENST00000508591.5	c.1036T>A	p.Leu346Met	missense_variant, NMD_transcript_variant	3/17	1		ENSP00000424186

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 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: 0.00

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	0.097
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0048	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.052	T;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.97	D;D
Vest4		0.61
MutPred		0.80		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.56
MPC		0.37
ClinPred		0.95	D
GERP RS		-6.4
Varity_R		0.31
gMVP		0.43

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: rs13141136; hg19: chr4-84370091;