chr8-78686566-G-A

Variant names:

• chr8-78686566-G-A
• rs1433232139
• NM_016010.3:c.310G>A

Variant summary

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

The NM_016010.3(ZC2HC1A):​c.310G>A​(p.Gly104Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,379,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.36
• Publications: 1 publications found

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]

IL7 Gene-Disease associations (from GenCC):

• epidermodysplasia verruciformis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• epidermodysplasia verruciformis, susceptibility to, 5

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC2HC1A	NM_016010.3	c.310G>A	p.Gly104Ser	missense_variant	Exon 4 of 9	ENST00000263849.9	NP_057094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC2HC1A	ENST00000263849.9	c.310G>A	p.Gly104Ser	missense_variant	Exon 4 of 9	1	NM_016010.3	ENSP00000263849.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1379878 Hom.: 0 Cov.: 31 AF XY: 0.00000292 AC XY: 2 AN XY: 684368

African (AFR) AF: 0.00 AC: 0 AN: 29784

American (AMR) AF: 0.00 AC: 0 AN: 37324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23888

East Asian (EAS) AF: 0.00 AC: 0 AN: 36006

South Asian (SAS) AF: 0.00 AC: 0 AN: 69812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5436

European-Non Finnish (NFE) AF: 0.00000374 AC: 4 AN: 1070480

Other (OTH) AF: 0.00 AC: 0 AN: 56290

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000823 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310G>A (p.G104S) alteration is located in exon 4 (coding exon 4) of the ZC2HC1A gene. This alteration results from a G to A substitution at nucleotide position 310, causing the glycine (G) at amino acid position 104 to be replaced by a serine (S). 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	0.69
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.019	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.69
MVP		0.66
MPC		0.49
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.67
gMVP		0.61
Mutation Taster		=51/49	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: rs1433232139; hg19: chr8-79598801;