19-5455948-C-G

Variant names:

• chr19-5455948-C-G
• rs771662701
• NM_181710.4:c.457C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181710.4(ZNRF4):​c.457C>G​(p.Arg153Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R153H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNRF4 NM_181710.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.531
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02554524).

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.457C>G	p.Arg153Gly	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.457C>G	p.Arg153Gly	missense	Exon 1 of 1	ENSP00000222033.4	Q8WWF5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448396 Hom.: 0 Cov.: 95 AF XY: 0.00 AC XY: 0 AN XY: 720978

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111420

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.10
DANN	Benign	0.62
DEOGEN2	Benign	0.00058	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.53
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.98	N
REVEL	Benign	0.013
Sift	Benign	0.66	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.45		Loss of solvent accessibility (P = 0.0159)
MVP		0.014
MPC		0.31
ClinPred		0.099	T
GERP RS		-7.2
Varity_R		0.043
gMVP		0.69
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs771662701; hg19: chr19-5455959;