Genetic Variant NM_001206998.2:c.69C>A (chr22-28883835-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001206998.2(ZNRF3):c.69C>A(p.Pro23Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000688 in 145,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P23P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNRF3
NM_001206998.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.315

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

ZNRF3 links:

ENSG00000302057 (HGNC:):

ENSG00000302057 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP7

Synonymous conserved (PhyloP=-0.315 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206998.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF3	NM_001206998.2	MANE Select	c.69C>A	p.Pro23Pro	synonymous	Exon 1 of 9	NP_001193927.1	Q9ULT6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNRF3	ENST00000544604.7	TSL:1 MANE Select	c.69C>A	p.Pro23Pro	synonymous	Exon 1 of 9	ENSP00000443824.2	Q9ULT6-1
ZNRF3	ENST00000920451.1		c.69C>A	p.Pro23Pro	synonymous	Exon 1 of 9	ENSP00000590510.1
ZNRF3	ENST00000920452.1		c.69C>A	p.Pro23Pro	synonymous	Exon 1 of 8	ENSP00000590511.1

Frequencies

GnomAD3 genomes

AF:

0.00000688

AC:

AN:

145454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000200

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

833924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

385178

African (AFR)

AF:

0.00

AC:

AN:

15792

American (AMR)

AF:

0.00

AC:

AN:

992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5154

East Asian (EAS)

AF:

0.00

AC:

AN:

3630

South Asian (SAS)

AF:

0.00

AC:

AN:

17146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

761994

Other (OTH)

AF:

0.00

AC:

AN:

27308

GnomAD4 genome

AF:

0.00000688

AC:

AN:

145454

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70708

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40600

American (AMR)

AF:

0.00

AC:

AN:

14660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.000200

AC:

AN:

4994

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8228

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65594

Other (OTH)

AF:

0.00

AC:

AN:

2010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.8

(source)

DANN

Benign

0.92

PhyloP100

-0.32

PromoterAI

-0.012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over