20-63559331-C-T

Variant names:

• chr20-63559331-C-T
• rs1394285265
• NM_001037335.2:c.7865G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001037335.2(HELZ2):​c.7865G>A​(p.Ser2622Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,601,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2622T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HELZ2 NM_001037335.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.579
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29916948).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001037335.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELZ2	NM_001037335.2	MANE Select	c.7865G>A	p.Ser2622Asn	missense	Exon 20 of 20	NP_001032412.2	Q9BYK8
	HELZ2	NM_033405.3		c.6158G>A	p.Ser2053Asn	missense	Exon 14 of 14	NP_208384.3	Q9BYK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HELZ2	ENST00000467148.2	TSL:1 MANE Select	c.7865G>A	p.Ser2622Asn	missense	Exon 20 of 20	ENSP00000417401.1	A0AAA9XBX5
	HELZ2	ENST00000850915.1		c.8606G>A	p.Ser2869Asn	missense	Exon 20 of 20	ENSP00000520998.1
	HELZ2	ENST00000427522.7		n.6582G>A		non_coding_transcript_exon	Exon 14 of 14

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449716 Hom.: 0 Cov.: 33 AF XY: 0.00000139 AC XY: 1 AN XY: 719564

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 43578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 84784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4932

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106348

Other (OTH) AF: 0.00 AC: 0 AN: 59808

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.14
Sift	Benign	0.038	D
Sift4G	Uncertain	0.013	D
Polyphen		0.011	B
Vest4		0.087
MutPred		0.40		Loss of stability (P = 0.0484)
MVP		0.43
MPC		0.19
ClinPred		0.18	T
GERP RS		3.5
Varity_R		0.037
gMVP		0.20
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1394285265; hg19: chr20-62190684;