Genetic Variant HELZ2:p.Thr1904Met (chr20-63563111-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001037335.2(HELZ2):c.5711C>T(p.Thr1904Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,595,312 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00058 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0010 ( 47 hom. )

Consequence

HELZ2
NM_001037335.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.380

Publications

9 publications found

Variant links:

Genes affected

HELZ2 (HGNC:30021): (helicase with zinc finger 2) The protein encoded by this gene is a nuclear transcriptional co-activator for peroxisome proliferator activated receptor alpha. The encoded protein contains a zinc finger and is a helicase that appears to be part of the peroxisome proliferator activated receptor alpha interacting complex. This gene is a member of the DNA2/NAM7 helicase gene family. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

HELZ2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00736928).

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00105 (1513/1443012) while in subpopulation EAS AF = 0.0371 (1437/38754). AF 95% confidence interval is 0.0355. There are 47 homozygotes in GnomAdExome4. There are 746 alleles in the male GnomAdExome4 subpopulation. Median coverage is 73. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HELZ2	NM_001037335.2 link	c.5711C>T	p.Thr1904Met	missense_variant	Exon 9 of 20	ENST00000467148.2	NP_001032412.2	Q9BYK8-1
HELZ2	NM_033405.3 link	c.4004C>T	p.Thr1335Met	missense_variant	Exon 3 of 14		NP_208384.3	Q9BYK8-2
HELZ2	XM_024452006.2 link	c.5711C>T	p.Thr1904Met	missense_variant	Exon 8 of 18		XP_024307774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HELZ2	ENST00000467148.2 link	c.5711C>T	p.Thr1904Met	missense_variant	Exon 9 of 20	1	NM_001037335.2	ENSP00000417401.1	Q9BYK8-1
HELZ2	ENST00000850915.1 link	c.6452C>T	p.Thr2151Met	missense_variant	Exon 9 of 20			ENSP00000520998.1
HELZ2	ENST00000427522.7 link	n.4428C>T		non_coding_transcript_exon_variant	Exon 3 of 14				Q9BYK8-2

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0166

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

GnomAD2 exomes

AF:

0.000893

AC:

186

AN:

208388

AF XY:

0.000904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000643

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000760

Gnomad OTH exome

AF:

0.000383

GnomAD4 exome

AF:

0.00105

AC:

1513

AN:

1443012

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

746

AN XY:

716554

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33134

American (AMR)

AF:

0.0000472

AC:

AN:

42416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.0371

AC:

1437

AN:

38754

South Asian (SAS)

AF:

0.000465

AC:

AN:

83814

European-Finnish (FIN)

AF:

0.0000408

AC:

AN:

48996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000815

AC:

AN:

1104794

Other (OTH)

AF:

0.000386

AC:

AN:

59640

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

116

233

349

466

582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000584

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0166

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.000896

AC:

107

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.076

.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

2.0

.;M

PhyloP100

0.38

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.2

D;D

REVEL

Benign

0.12

Sift

Benign

0.080

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.60

P;P

Vest4

0.11

MVP

0.35

MPC

0.62

ClinPred

0.038

GERP RS

-0.21

Varity_R

0.025

gMVP

0.29

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over