22-29049779-A-G

Variant summary

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

The NM_001206998.2(ZNRF3):c.1598A>G(p.His533Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,388 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

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.1598A>G	p.His533Arg	missense_variant	8/9	ENST00000544604.7
ZNRF3	NM_032173.4	c.1298A>G	p.His433Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7	c.1598A>G	p.His533Arg	missense_variant	8/9	1	NM_001206998.2	A2
ZNRF3	ENST00000406323.3	c.1298A>G	p.His433Arg	missense_variant	7/8	1		P2
ZNRF3	ENST00000402174.5	c.1298A>G	p.His433Arg	missense_variant	8/9	2		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447388 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 718054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 11, 2022

The c.1598A>G (p.H533R) alteration is located in exon 8 (coding exon 8) of the ZNRF3 gene. This alteration results from a A to G substitution at nucleotide position 1598, causing the histidine (H) at amino acid position 533 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.35	T;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.2	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.081	T;T;T
Sift4G	Uncertain	0.027	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.76
MutPred		0.32		Gain of solvent accessibility (P = 0.0044);.;.;
MVP		0.63
MPC		1.3
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.41
gMVP		0.63

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: rs1157956367; hg19: chr22-29445767;