8-78689371-G-T

Variant names:

• chr8-78689371-G-T
• rs574401853
• NM_016010.3:c.502G>T

Variant summary

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

The NM_016010.3(ZC2HC1A):​c.502G>T​(p.Val168Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,425,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZC2HC1A NM_016010.3 missense, splice_region
• Scores: Splicing: ADA: 0.006249
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.21
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC2HC1A	NM_016010.3	c.502G>T	p.Val168Leu	missense_variant, splice_region_variant	Exon 5 of 9	ENST00000263849.9	NP_057094.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC2HC1A	ENST00000263849.9	c.502G>T	p.Val168Leu	missense_variant, splice_region_variant	Exon 5 of 9	1	NM_016010.3	ENSP00000263849.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1425090 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 708556

African (AFR) AF: 0.00 AC: 0 AN: 31262

American (AMR) AF: 0.00 AC: 0 AN: 38624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24790

East Asian (EAS) AF: 0.00 AC: 0 AN: 38036

South Asian (SAS) AF: 0.00 AC: 0 AN: 79580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096092

Other (OTH) AF: 0.0000511 AC: 3 AN: 58754

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		9.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.23
Sift	Benign	0.36	T
Sift4G	Benign	0.74	T
Polyphen		0.98	D
Vest4		0.60
MutPred		0.17		Loss of ubiquitination at K170 (P = 0.0919);
MVP		0.31
MPC		0.093
ClinPred		0.47	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.14
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0062
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		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: rs574401853; hg19: chr8-79601606;