4-83427612-T-A

Variant names:

• chr4-83427612-T-A
• rs113520876
• NM_133636.5:c.2627A>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_133636.5(HELQ):​c.2627A>T​(p.Tyr876Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,604,092 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: HELQ NM_133636.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 8.00

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 4-83427612-T-A is Benign according to our data. Variant chr4-83427612-T-A is described in ClinVar as [Benign]. Clinvar id is 3038702.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1769/152302) while in subpopulation AFR AF = 0.0408 (1696/41566). AF 95% confidence interval is 0.0392. There are 29 homozygotes in GnomAd4. There are 835 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELQ	NM_133636.5	c.2627A>T	p.Tyr876Phe	missense_variant	Exon 13 of 18	ENST00000295488.8	NP_598375.3
HELQ	NM_001297755.2	c.2426A>T	p.Tyr809Phe	missense_variant	Exon 12 of 17		NP_001284684.2
HELQ	NM_001297756.2	c.1136A>T	p.Tyr379Phe	missense_variant	Exon 13 of 18		NP_001284685.1
HELQ	NM_001297757.2	c.995A>T	p.Tyr332Phe	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	c.2627A>T	p.Tyr876Phe	missense_variant	Exon 13 of 18	1	NM_133636.5	ENSP00000295488.3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152184 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00295 AC: 713 AN: 241480 AF XY: 0.00192

Gnomad AFR exome AF: 0.0420

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.00113 AC: 1636 AN: 1451790 Hom.: 26 Cov.: 29 AF XY: 0.000982 AC XY: 709 AN XY: 722184

Gnomad4 AFR exome AF: 0.0406 AC: 1325 AN: 32666

Gnomad4 AMR exome AF: 0.00171 AC: 73 AN: 42780

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25872

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38952

Gnomad4 SAS exome AF: 0.000142 AC: 12 AN: 84440

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53282

Gnomad4 NFE exome AF: 0.0000361 AC: 40 AN: 1108094

Gnomad4 Remaining exome AF: 0.00282 AC: 169 AN: 59972

GnomAD4 genome AF: 0.0116 AC: 1769 AN: 152302 Hom.: 29 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74488

Gnomad4 AFR AF: 0.0408 AC: 0.0408026 AN: 0.0408026

Gnomad4 AMR AF: 0.00359 AC: 0.00359477 AN: 0.00359477

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000414 AC: 0.000414079 AN: 0.000414079

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000588 AC: 0.0000588149 AN: 0.0000588149

Gnomad4 OTH AF: 0.00473 AC: 0.0047259 AN: 0.0047259

Alfa AF: 0.000499 Hom.: 1

Bravo AF: 0.0132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0429 AC: 189

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HELQ-related disorder Benign:1

Mar 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	0.16
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.28
Sift	Benign	0.18	T;T
Sift4G	Benign	0.23	T;T
Polyphen		0.40	B;D
Vest4		0.65
MVP		0.81
MPC		0.13
ClinPred		0.042	T
GERP RS		5.6
Varity_R		0.34
gMVP		0.44
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113520876; hg19: chr4-84348765; COSMIC: COSV99040416;