8-78698475-A-G

Variant names:

• chr8-78698475-A-G
• rs1054283
• NM_016010.3:c.666A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP7 BA1

The NM_016010.3(ZC2HC1A):​c.666A>G​(p.Leu222Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.739 in 1,610,586 control chromosomes in the GnomAD database, including 443,631 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (36586 hom., cov: 32)
  • Exomes 𝑓: 0.74 (407045 hom.)
• Consequence: ZC2HC1A NM_016010.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.377
• Publications: 31 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.284).
• BP7: Synonymous conserved (PhyloP=0.377 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC2HC1A	NM_016010.3	c.666A>G	p.Leu222Leu	synonymous_variant	Exon 7 of 9	ENST00000263849.9	NP_057094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC2HC1A	ENST00000263849.9	c.666A>G	p.Leu222Leu	synonymous_variant	Exon 7 of 9	1	NM_016010.3	ENSP00000263849.3

Frequencies

GnomAD3 genomes AF: 0.686 AC: 104184 AN: 151916 Hom.: 36568 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.743 AC: 185922 AN: 250396 AF XY: 0.742

Gnomad AFR exome AF: 0.535

Gnomad AMR exome AF: 0.835

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.911

Gnomad FIN exome AF: 0.723

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.745 AC: 1086231 AN: 1458552 Hom.: 407045 Cov.: 40 AF XY: 0.745 AC XY: 540429 AN XY: 725712

African (AFR) AF: 0.530 AC: 17698 AN: 33364

American (AMR) AF: 0.824 AC: 36743 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 15123 AN: 26076

East Asian (EAS) AF: 0.919 AC: 36417 AN: 39616

South Asian (SAS) AF: 0.760 AC: 65338 AN: 86008

European-Finnish (FIN) AF: 0.730 AC: 38930 AN: 53348

Middle Eastern (MID) AF: 0.610 AC: 3506 AN: 5744

European-Non Finnish (NFE) AF: 0.747 AC: 828915 AN: 1109576

Other (OTH) AF: 0.723 AC: 43561 AN: 60232

GnomAD4 genome AF: 0.686 AC: 104246 AN: 152034 Hom.: 36586 Cov.: 32 AF XY: 0.688 AC XY: 51104 AN XY: 74292

African (AFR) AF: 0.535 AC: 22164 AN: 41454

American (AMR) AF: 0.750 AC: 11458 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1976 AN: 3470

East Asian (EAS) AF: 0.906 AC: 4694 AN: 5180

South Asian (SAS) AF: 0.765 AC: 3684 AN: 4818

European-Finnish (FIN) AF: 0.738 AC: 7803 AN: 10572

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50193 AN: 67958

Other (OTH) AF: 0.667 AC: 1407 AN: 2110

Alfa AF: 0.715 Hom.: 117683

Bravo AF: 0.683

Asia WGS AF: 0.793 AC: 2754 AN: 3476

EpiCase AF: 0.722

EpiControl AF: 0.715

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1054283; hg19: chr8-79610710; COSMIC: COSV55670563; COSMIC: COSV55670563;