NM_016010.3:c.517G>T

Variant names:

• chr8-78697419-G-T
• rs138000597
• NM_016010.3:c.517G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016010.3(ZC2HC1A):​c.517G>T​(p.Ala173Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,443,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A173T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06639421).

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.517G>T	p.Ala173Ser	missense	Exon 6 of 9	NP_057094.2	Q96GY0
	ZC2HC1A	NM_001362969.2		c.517G>T	p.Ala173Ser	missense	Exon 6 of 10	NP_001349898.1	H0YAP0
	ZC2HC1A	NR_156423.2		n.577G>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.517G>T	p.Ala173Ser	missense	Exon 6 of 9	ENSP00000263849.3	Q96GY0
	ZC2HC1A	ENST00000519307.2	TSL:5	c.517G>T	p.Ala173Ser	missense	Exon 6 of 10	ENSP00000427797.2	H0YAP0
	ZC2HC1A	ENST00000874954.1		c.514G>T	p.Ala172Ser	missense	Exon 6 of 9	ENSP00000545013.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 234528 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: 0.00000346 AC: 5 AN: 1443590 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 718026

African (AFR) AF: 0.00 AC: 0 AN: 32166

American (AMR) AF: 0.0000251 AC: 1 AN: 39836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25704

East Asian (EAS) AF: 0.00 AC: 0 AN: 38754

South Asian (SAS) AF: 0.00 AC: 0 AN: 82674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1105854

Other (OTH) AF: 0.00 AC: 0 AN: 59640

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.016
Sift	Benign	0.52	T
Sift4G	Benign	0.57	T
Polyphen		0.11	B
Vest4		0.42
MutPred		0.10		Gain of phosphorylation at A173 (P = 0.0111)
MVP		0.082
MPC		0.098
ClinPred		0.065	T
GERP RS		2.7
PromoterAI		0.0070	Neutral
Varity_R		0.034
gMVP		0.19
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138000597; hg19: chr8-79609654;