22-29043380-G-T

Variant names:

• chr22-29043380-G-T
• NM_001206998.2:c.583G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001206998.2(ZNRF3):​c.583G>T​(p.Val195Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.33

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.583G>T	p.Val195Phe	missense_variant	Exon 4 of 9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.283G>T	p.Val95Phe	missense_variant	Exon 4 of 9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.583G>T	p.Val195Phe	missense_variant	Exon 4 of 9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.283G>T	p.Val95Phe	missense_variant	Exon 3 of 8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.283G>T	p.Val95Phe	missense_variant	Exon 4 of 9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.583G>T (p.V195F) alteration is located in exon 4 (coding exon 4) of the ZNRF3 gene. This alteration results from a G to T substitution at nucleotide position 583, causing the valine (V) at amino acid position 195 to be replaced by a phenylalanine (F). 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	0.98
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.97	L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.39
Sift	Benign	0.059	T;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.45		Loss of helix (P = 0.079);.;.;
MVP		0.52
MPC		1.4
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.70
gMVP		0.96

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: chr22-29439368;