Genetic Variant ZNRF3:c.2768-90A>G (chr22-29053489-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001206998.2(ZNRF3):c.2768-90A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,288,702 control chromosomes in the GnomAD database, including 116,093 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.37 ( 11125 hom., cov: 31)

Exomes 𝑓: 0.43 ( 104968 hom. )

Consequence

ZNRF3
NM_001206998.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.29

Publications

35 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

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.2768-90A>G		intron	N/A	NP_001193927.1	Q9ULT6-1
	ZNRF3	NM_032173.4		c.2468-90A>G		intron	N/A	NP_115549.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ZNRF3	ENST00000544604.7	TSL:1 MANE Select	c.2768-90A>G	intron	N/A	ENSP00000443824.2	Q9ULT6-1
ZNRF3	ENST00000406323.3	TSL:1	c.2468-90A>G	intron	N/A	ENSP00000384553.3	Q9ULT6-2
ZNRF3	ENST00000920451.1		c.2768-54A>G	intron	N/A	ENSP00000590510.1

Frequencies

GnomAD3 genomes

AF:

0.366

AC:

55545

AN:

151806

Hom.:

11122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.204

Gnomad AMI

AF:

0.402

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.545

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.407

GnomAD4 exome

AF:

0.426

AC:

483741

AN:

1136778

Hom.:

104968

AF XY:

0.427

AC XY:

246444

AN XY:

576650

show subpopulations

African (AFR)

AF:

0.198

AC:

5232

AN:

26422

American (AMR)

AF:

0.396

AC:

14390

AN:

36332

Ashkenazi Jewish (ASJ)

AF:

0.550

AC:

11636

AN:

21144

East Asian (EAS)

AF:

0.488

AC:

18316

AN:

37548

South Asian (SAS)

AF:

0.463

AC:

33522

AN:

72352

European-Finnish (FIN)

AF:

0.396

AC:

20313

AN:

51238

Middle Eastern (MID)

AF:

0.509

AC:

2288

AN:

4496

European-Non Finnish (NFE)

AF:

0.426

AC:

356970

AN:

838344

Other (OTH)

AF:

0.431

AC:

21074

AN:

48902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

13110

26219

39329

52438

65548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9958

19916

29874

39832

49790

<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:

0.366

AC:

55551

AN:

151924

Hom.:

11125

Cov.:

AF XY:

0.369

AC XY:

27398

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.203

AC:

8435

AN:

41452

American (AMR)

AF:

0.426

AC:

6511

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

1890

AN:

3466

East Asian (EAS)

AF:

0.461

AC:

2378

AN:

5158

South Asian (SAS)

AF:

0.467

AC:

2240

AN:

4794

European-Finnish (FIN)

AF:

0.401

AC:

4238

AN:

10560

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.420

AC:

28509

AN:

67916

Other (OTH)

AF:

0.405

AC:

854

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1698

3397

5095

6794

8492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

544

1088

1632

2176

2720

<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:

0.410

Hom.:

56380

Bravo

AF:

0.359

Asia WGS

AF:

0.435

AC:

1515

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.025

(source)

DANN

Benign

0.50

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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