8-78686584-C-T

Variant names:

• chr8-78686584-C-T
• rs1050746454
• NM_016010.3:c.328C>T

Variant summary

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

The NM_016010.3(ZC2HC1A):​c.328C>T​(p.Pro110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000008 in 1,375,370 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: 0.0000080 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38
• Publications: 0 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

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.328C>T	p.Pro110Ser	missense	Exon 4 of 9	NP_057094.2	Q96GY0
	ZC2HC1A	NM_001362969.2		c.328C>T	p.Pro110Ser	missense	Exon 4 of 10	NP_001349898.1	H0YAP0
	ZC2HC1A	NR_156423.2		n.388C>T		non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC2HC1A	ENST00000263849.9	TSL:1 MANE Select	c.328C>T	p.Pro110Ser	missense	Exon 4 of 9	ENSP00000263849.3	Q96GY0
	ZC2HC1A	ENST00000519307.2	TSL:5	c.328C>T	p.Pro110Ser	missense	Exon 4 of 10	ENSP00000427797.2	H0YAP0
	ZC2HC1A	ENST00000874954.1		c.328C>T	p.Pro110Ser	missense	Exon 4 of 9	ENSP00000545013.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000800 AC: 11 AN: 1375370 Hom.: 0 Cov.: 31 AF XY: 0.0000117 AC XY: 8 AN XY: 681990

African (AFR) AF: 0.00 AC: 0 AN: 29436

American (AMR) AF: 0.00 AC: 0 AN: 35580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23482

East Asian (EAS) AF: 0.000111 AC: 4 AN: 36172

South Asian (SAS) AF: 0.00 AC: 0 AN: 68678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00000654 AC: 7 AN: 1069684

Other (OTH) AF: 0.00 AC: 0 AN: 56118

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.97
BayesDel_addAF	Benign	0.0088	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.098	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.012	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.44		Gain of phosphorylation at P110 (P = 0.0108)
MVP		0.31
MPC		0.50
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.61
gMVP		0.52
Mutation Taster		=49/51	disease causing

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: rs1050746454; hg19: chr8-79598819;