Genetic Variant NM_133636.5:c.2627A>G (chr4-83427612-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_133636.5(HELQ):c.2627A>G(p.Tyr876Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000081 in 1,604,000 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

HELQ
NM_133636.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.00

Variant links:

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]

HELQ links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELQ	NM_133636.5 link	c.2627A>G	p.Tyr876Cys	missense_variant	Exon 13 of 18	ENST00000295488.8	NP_598375.3	Q8TDG4-1
HELQ	NM_001297755.2 link	c.2426A>G	p.Tyr809Cys	missense_variant	Exon 12 of 17		NP_001284684.2
HELQ	NM_001297756.2 link	c.1136A>G	p.Tyr379Cys	missense_variant	Exon 13 of 18		NP_001284685.1
HELQ	NM_001297757.2 link	c.995A>G	p.Tyr332Cys	missense_variant	Exon 12 of 17		NP_001284686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HELQ	ENST00000295488.8 link	c.2627A>G	p.Tyr876Cys	missense_variant	Exon 13 of 18	1	NM_133636.5	ENSP00000295488.3		Q8TDG4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000828

AC:

AN:

241480

Hom.:

AF XY:

0.00000764

AC XY:

AN XY:

130856

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000314

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000575

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000827

AC:

AN:

1451810

Hom.:

Cov.:

AF XY:

0.00000969

AC XY:

AN XY:

722190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000467

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000180

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.087

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.057

MutationAssessor

Pathogenic

2.9

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;D

Vest4

0.90

MutPred

0.52

Loss of helix (P = 0.0033);.;

MVP

0.86

MPC

0.57

ClinPred

0.99

GERP RS

5.6

Varity_R

0.51

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over