chr22-29048441-C-G

Variant names:

• chr22-29048441-C-G
• NM_001206998.2:c.965C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001206998.2(ZNRF3):​c.965C>G​(p.Pro322Arg) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P322L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNRF3 NM_001206998.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a zinc_finger_region RING-type; atypical (size 41) in uniprot entity ZNRF3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001206998.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88
• PP5: Variant 22-29048441-C-G is Pathogenic according to our data. Variant chr22-29048441-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3238965.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF3	NM_001206998.2	c.965C>G	p.Pro322Arg	missense_variant	Exon 7 of 9	ENST00000544604.7	NP_001193927.1
ZNRF3	NM_032173.4	c.665C>G	p.Pro222Arg	missense_variant	Exon 7 of 9		NP_115549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF3	ENST00000544604.7	c.965C>G	p.Pro322Arg	missense_variant	Exon 7 of 9	1	NM_001206998.2	ENSP00000443824.2
ZNRF3	ENST00000406323.3	c.665C>G	p.Pro222Arg	missense_variant	Exon 6 of 8	1		ENSP00000384553.3
ZNRF3	ENST00000402174.5	c.665C>G	p.Pro222Arg	missense_variant	Exon 7 of 9	2		ENSP00000384456.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ZNRF3-related disorder Pathogenic:1

May 29, 2024

Institute of Medical Genetics, University of Zurich

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG criteria applied: PS3 (Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product), PM1 (Located in a mutational hot spot and/or critical and well-established functional domain), PM6 (assumed de novo), PM2 (absent from controls), PP3 (in silico programs predict a deleterious effect) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.027	D
MutationAssessor	Benign	-0.020	N;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.95
MutPred		0.49		Gain of MoRF binding (P = 0.0025);.;.;
MVP		0.84
MPC		1.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr22-29444429;