Genetic Variant ZNRF4:p.Pro6Arg (chr19-5455508-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181710.4(ZNRF4):c.17C>G(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ZNRF4
NM_181710.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.98

Publications

0 publications found

Variant links:

Genes affected

ZNRF4 (HGNC:17726): (zinc and ring finger 4) Predicted to enable ubiquitin protein ligase activity. Involved in ubiquitin-dependent protein catabolic process. Located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNRF4 links:

ENSG00000297997 (HGNC:):

ENSG00000297997 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0744794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181710.4. 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
	ZNRF4	NM_181710.4	MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 1	NP_859061.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNRF4	ENST00000222033.6	TSL:6 MANE Select	c.17C>G	p.Pro6Arg	missense	Exon 1 of 1	ENSP00000222033.4	Q8WWF5
	ENSG00000297997	ENST00000752382.1		n.-173G>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245110

AF XY:

0.00000751

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1457330

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25784

East Asian (EAS)

AF:

0.00

AC:

AN:

39630

South Asian (SAS)

AF:

0.00

AC:

AN:

85842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110222

Other (OTH)

AF:

0.0000166

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.50

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0026

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0015

LIST_S2

Benign

0.28

M_CAP

Benign

0.0091

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.55

PhyloP100

-5.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.48

REVEL

Benign

0.020

Sift

Benign

0.030

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.041

MutPred

0.32

Gain of MoRF binding (P = 2e-04)

MVP

0.030

MPC

0.27

ClinPred

0.11

GERP RS

-5.6

PromoterAI

0.0072

Neutral

(source)

Varity_R

0.065

gMVP

0.24

Mutation Taster

=98/2

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over