Variant chr22-29046756-T-C details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001206998.2(ZNRF3):c.785T>C(p.Met262Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,124 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: 0.0000027 ( 0 hom. )

Consequence

ZNRF3
NM_001206998.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Variant links:

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]

ZNRF3 links:

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ACMG classification

Classification made for transcript

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	Protein	UniProt
ZNRF3	NM_001206998.2 link	c.785T>C	p.Met262Thr	missense_variant	6/9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4 link	c.485T>C	p.Met162Thr	missense_variant	6/9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNRF3	ENST00000544604.7 link	c.785T>C	p.Met262Thr	missense_variant	6/9	1	NM_001206998.2	ENSP00000443824.2	Q9ULT6-1
ZNRF3	ENST00000406323.3 link	c.485T>C	p.Met162Thr	missense_variant	5/8	1		ENSP00000384553.3	Q9ULT6-2
ZNRF3	ENST00000402174.5 link	c.485T>C	p.Met162Thr	missense_variant	6/9	2		ENSP00000384456.1	Q9ULT6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247672

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1459124

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725686

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000225

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2023

The c.785T>C (p.M262T) alteration is located in exon 6 (coding exon 6) of the ZNRF3 gene. This alteration results from a T to C substitution at nucleotide position 785, causing the methionine (M) at amino acid position 262 to be replaced by a threonine (T). 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.038

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.43

Sift

Uncertain

0.0070

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.70

P;.;.

Vest4

0.81

MutPred

0.39

Gain of helix (P = 0.0078);.;.;

MVP

0.67

MPC

1.1

ClinPred

0.87

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.51

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over