8-78697440-C-T

Variant names:

• chr8-78697440-C-T
• rs769083996
• NM_016010.3:c.538C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016010.3(ZC2HC1A):​c.538C>T​(p.Pro180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000087 in 1,608,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.32
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17508185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016010.3. 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
	ZC2HC1A	NM_016010.3	MANE Select	c.538C>T	p.Pro180Ser	missense	Exon 6 of 9	NP_057094.2	Q96GY0
	ZC2HC1A	NM_001362969.2		c.538C>T	p.Pro180Ser	missense	Exon 6 of 10	NP_001349898.1	H0YAP0
	ZC2HC1A	NR_156423.2		n.598C>T		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC2HC1A	ENST00000263849.9	TSL:1 MANE Select	c.538C>T	p.Pro180Ser	missense	Exon 6 of 9	ENSP00000263849.3	Q96GY0
	ZC2HC1A	ENST00000519307.2	TSL:5	c.538C>T	p.Pro180Ser	missense	Exon 6 of 10	ENSP00000427797.2	H0YAP0
	ZC2HC1A	ENST00000874954.1		c.535C>T	p.Pro179Ser	missense	Exon 6 of 9	ENSP00000545013.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152122 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 246248 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000824 AC: 12 AN: 1456524 Hom.: 0 Cov.: 30 AF XY: 0.00000966 AC XY: 7 AN XY: 724592

⚠️ 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: 33046

American (AMR) AF: 0.00 AC: 0 AN: 42890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1110572

Other (OTH) AF: 0.00 AC: 0 AN: 60198

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000280261), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

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	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.074
Sift	Benign	0.095	T
Sift4G	Uncertain	0.037	D
Polyphen		0.54	P
Vest4		0.42
MutPred		0.23		Gain of phosphorylation at P180 (P = 0.0055)
MVP		0.043
MPC		0.10
ClinPred		0.92	D
GERP RS		5.5
PromoterAI		0.0022	Neutral
Varity_R		0.13
gMVP		0.25
Mutation Taster		=89/11	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: rs769083996; hg19: chr8-79609675;