4-83407479-C-T

Position:

• chr4-83407479-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_133636.5(HELQ):​c.3280G>A​(p.Val1094Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.006 in 1,607,490 control chromosomes in the GnomAD database, including 491 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.031 (255 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (236 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0100

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040671825).
• BP6: Variant 4-83407479-C-T is Benign according to our data. Variant chr4-83407479-C-T is described in ClinVar as [Benign]. Clinvar id is 3037625.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HELQ	NM_133636.5	c.3280G>A	p.Val1094Met	missense_variant	18/18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.3079G>A	p.Val1027Met	missense_variant	17/17		NP_001284684.2
HELQ	NM_001297756.2	c.1789G>A	p.Val597Met	missense_variant	18/18		NP_001284685.1
HELQ	NM_001297757.2	c.1648G>A	p.Val550Met	missense_variant	17/17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8	c.3280G>A	p.Val1094Met	missense_variant	18/18	1	NM_133636.5	ENSP00000295488	P1
HELQ	ENST00000510985.1	c.3079G>A	p.Val1027Met	missense_variant	17/17	1		ENSP00000424539
HELQ	ENST00000508591.5	c.*1712G>A		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000424186
HELQ	ENST00000512539.1	n.519G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4698 AN: 152182 Hom.: 250 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000602

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00813 AC: 1992 AN: 244962 Hom.: 99 AF XY: 0.00596 AC XY: 790 AN XY: 132628

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.00551

Gnomad ASJ exome AF: 0.000500

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000442

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000500

Gnomad OTH exome AF: 0.00322

GnomAD4 exome AF: 0.00339 AC: 4926 AN: 1455190 Hom.: 236 Cov.: 29 AF XY: 0.00300 AC XY: 2174 AN XY: 723814

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00659

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000519

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000424

Gnomad4 OTH exome AF: 0.00805

GnomAD4 genome AF: 0.0310 AC: 4722 AN: 152300 Hom.: 255 Cov.: 32 AF XY: 0.0300 AC XY: 2233 AN XY: 74470

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.00565 Hom.: 92

Bravo AF: 0.0345

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.111 AC: 489

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0102 AC: 1239

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000554

EpiControl AF: 0.000963

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HELQ-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.9
DANN	Benign	0.88
DEOGEN2	Benign	0.00057	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.080
Sift	Benign	0.19	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0	B;B
Vest4		0.063
MPC		0.11
ClinPred		0.0077	T
GERP RS		0.38
Varity_R		0.034
gMVP		0.22

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: rs17006794; hg19: chr4-84328632;