Genetic Variant NM_001206998.2:c.69C>G (chr22-28883835-C-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001206998.2(ZNRF3):c.69C>G(p.Pro23Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000421 in 979,426 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

ZNRF3
NM_001206998.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 22-28883835-C-G is Benign according to our data. Variant chr22-28883835-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2653039.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

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

BS2

High AC in GnomAd4 at 156 AD gene.

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>G	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>G	p.Pro23Pro	synonymous	Exon 1 of 9	ENSP00000443824.2	Q9ULT6-1
ZNRF3	ENST00000920451.1		c.69C>G	p.Pro23Pro	synonymous	Exon 1 of 9	ENSP00000590510.1
ZNRF3	ENST00000920452.1		c.69C>G	p.Pro23Pro	synonymous	Exon 1 of 8	ENSP00000590511.1

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

156

AN:

145452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000205

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00314

Gnomad FIN

AF:

0.00498

Gnomad MID

AF:

0.00333

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.000995

GnomAD4 exome

AF:

0.000307

AC:

256

AN:

833926

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

114

AN XY:

385180

show subpopulations

African (AFR)

AF:

0.0000633

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:

0.00525

AC:

AN:

17148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

286

Middle Eastern (MID)

AF:

0.000617

AC:

AN:

1622

European-Non Finnish (NFE)

AF:

0.000198

AC:

151

AN:

761994

Other (OTH)

AF:

0.000476

AC:

AN:

27308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00107

AC:

156

AN:

145500

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

70770

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40684

American (AMR)

AF:

0.000204

AC:

AN:

14678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4976

South Asian (SAS)

AF:

0.00315

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.00498

AC:

AN:

8228

Middle Eastern (MID)

AF:

0.00365

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

65580

Other (OTH)

AF:

0.000986

AC:

AN:

2028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00254

Hom.:

Bravo

AF:

0.000351

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

9.9

(source)

DANN

Benign

0.82

PhyloP100

-0.32

PromoterAI

0.085

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over