chr20-63560324-G-T

Variant names:

• chr20-63560324-G-T
• rs377556489
• NM_001037335.2:c.7504C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001037335.2(HELZ2):​c.7504C>A​(p.Arg2502Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,816 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2502C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: HELZ2 NM_001037335.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.7504C>A	p.Arg2502Ser	missense	Exon 18 of 20	NP_001032412.2	Q9BYK8
	HELZ2	NM_033405.3		c.5797C>A	p.Arg1933Ser	missense	Exon 12 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.7504C>A	p.Arg2502Ser	missense	Exon 18 of 20	ENSP00000417401.1	A0AAA9XBX5
	HELZ2	ENST00000850915.1		c.8245C>A	p.Arg2749Ser	missense	Exon 18 of 20	ENSP00000520998.1
	HELZ2	ENST00000427522.7		n.6221C>A		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399816 Hom.: 0 Cov.: 38 AF XY: 0.00000145 AC XY: 1 AN XY: 691076

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32106

American (AMR) AF: 0.00 AC: 0 AN: 37562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23168

East Asian (EAS) AF: 0.00 AC: 0 AN: 38460

South Asian (SAS) AF: 0.00 AC: 0 AN: 78428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4994

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085472

Other (OTH) AF: 0.00 AC: 0 AN: 58092

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	0.038
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.3
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.57
Sift	Benign	0.032	D
Sift4G	Benign	0.36	T
Polyphen		0.84	P
Vest4		0.54
MutPred		0.49		Gain of catalytic residue at Q2506 (P = 0.0369)
MVP		0.58
MPC		0.40
ClinPred		0.63	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.76
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs377556489; hg19: chr20-62191677;