22-29049328-A-G

Variant summary

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

The NM_001206998.2(ZNRF3):c.1147A>G(p.Thr383Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,638 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: 0.0000021 (0 hom.)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04

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.1147A>G	p.Thr383Ala	missense_variant	8/9	ENST00000544604.7
ZNRF3	NM_032173.4	c.847A>G	p.Thr283Ala	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNRF3	ENST00000544604.7	c.1147A>G	p.Thr383Ala	missense_variant	8/9	1	NM_001206998.2	A2
ZNRF3	ENST00000406323.3	c.847A>G	p.Thr283Ala	missense_variant	7/8	1		P2
ZNRF3	ENST00000402174.5	c.847A>G	p.Thr283Ala	missense_variant	8/9	2		P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727144

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 27, 2021

The c.1147A>G (p.T383A) 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 1147, causing the threonine (T) at amino acid position 383 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.079	T;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	0.89	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		0.93	P;.;.
Vest4		0.63
MutPred		0.16		Loss of glycosylation at T383 (P = 0.0152);.;.;
MVP		0.46
MPC		0.77
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.071
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-29445316;