22-29049592-C-T

Variant summary

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

The NM_001206998.2(ZNRF3):c.1411C>T(p.His471Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

Genes affected

ZNRF3 (HGNC:18126): (zinc and ring finger 3) Enables frizzled binding activity and ubiquitin-protein transferase activity. Involved in cellular protein metabolic process and negative regulation of Wnt signaling pathway. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNRF3	NM_001206998.2	c.1411C>T	p.His471Tyr	missense_variant	8/9	ENST00000544604.7
ZNRF3	NM_032173.4	c.1111C>T	p.His371Tyr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7	c.1411C>T	p.His471Tyr	missense_variant	8/9	1	NM_001206998.2	A2
ZNRF3	ENST00000406323.3	c.1111C>T	p.His371Tyr	missense_variant	7/8	1		P2
ZNRF3	ENST00000402174.5	c.1111C>T	p.His371Tyr	missense_variant	8/9	2		P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456468 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724472

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000826 AC: 1

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

Jul 21, 2021

The c.1411C>T (p.H471Y) alteration is located in exon 8 (coding exon 8) of the ZNRF3 gene. This alteration results from a C to T substitution at nucleotide position 1411, causing the histidine (H) at amino acid position 471 to be replaced by a tyrosine (Y). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.84
MutPred		0.32		Loss of helix (P = 0.0196);.;.;
MVP		0.23
MPC		1.2
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.81

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: rs745870049; hg19: chr22-29445580;