7-30285560-C-T

Position:

• chr7-30285560-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_147128.4(ZNRF2):​c.203C>T​(p.Ala68Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 835,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: ZNRF2 NM_147128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.504

Genes affected

ZNRF2 (HGNC:22316): (zinc and ring finger 2) Enables ubiquitin protein ligase activity. Predicted to be involved in protein ubiquitination. Located in cytoplasmic vesicle membrane; nuclear lumen; and plasma membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ZNRF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21194863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNRF2	NM_147128.4	c.203C>T	p.Ala68Val	missense_variant	1/5	ENST00000323037.5	NP_667339.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNRF2	ENST00000323037.5	c.203C>T	p.Ala68Val	missense_variant	1/5	1	NM_147128.4	ENSP00000323879.4
ZNRF2	ENST00000459998.1	n.-14C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.0000156 AC: 13 AN: 835110 Hom.: 0 Cov.: 29 AF XY: 0.0000181 AC XY: 7 AN XY: 385958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000292

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000656

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.203C>T (p.A68V) alteration is located in exon 1 (coding exon 1) of the ZNRF2 gene. This alteration results from a C to T substitution at nucleotide position 203, causing the alanine (A) at amino acid position 68 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.98	D
Vest4		0.26
MutPred		0.32		Gain of catalytic residue at A68 (P = 0.0649);
MVP		0.23
MPC		0.68
ClinPred		0.46	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.33

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

Publications

LitVar

Other links and lift over

dbSNP: rs1798763222; hg19: chr7-30325176;