8-78689309-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016010.3(ZC2HC1A):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,450,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46

Genes affected

ZC2HC1A (HGNC:24277): (zinc finger C2HC-type containing 1A) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

IL7 (HGNC:6023): (interleukin 7) The protein encoded by this gene is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. IL7 is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. IL7 plays an essential role in lymphoid cell survival, and in the maintenance of naive and memory T cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their presence in normal tissues has not been confirmed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can be a potent inducer of proinflammatory cytokines and chemokines which may defend against the infection, but may also mediate destructive lung injury. Elevated serum IL7 levels, together with several other circulating cytokines and chemokines, has been found to be associated with the severity of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC2HC1A	NM_016010.3	c.440G>A	p.Arg147His	missense_variant	5/9	ENST00000263849.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC2HC1A	ENST00000263849.9	c.440G>A	p.Arg147His	missense_variant	5/9	1	NM_016010.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000207 AC: 5 AN: 241778 Hom.: 0 AF XY: 0.0000153 AC XY: 2 AN XY: 130910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1450302 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 721388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.440G>A (p.R147H) alteration is located in exon 5 (coding exon 5) of the ZC2HC1A gene. This alteration results from a G to A substitution at nucleotide position 440, causing the arginine (R) at amino acid position 147 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.67		Loss of MoRF binding (P = 0.0053);
MVP		0.20
MPC		0.55
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.54
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs761443209; hg19: chr8-79601544; COSMIC: COSV55670361;