rs2036166043

Variant names:

• chr16-75093576-C-G
• rs2036166043
• NM_032268.5:c.429C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032268.5(ZNRF1):​c.429C>G​(p.Phe143Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNRF1 NM_032268.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

Genes affected

ZNRF1 (HGNC:18452): (zinc and ring finger 1) This gene encodes an E3 ubiquitin-protein ligase that plays a role in neural-cell differentiation. Overexpression of this gene causes neurite-like elongation. The encoded protein contains both a zinc finger and a RING finger motif and is localized in the endosome/lysosome compartment, indicating that it may be involved in ubiquitin-mediated protein modification, and in synaptic vessicle membranes in neurons. [provided by RefSeq, Feb 2012]

ACMG classification

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=0.2209734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNRF1	NM_032268.5	c.429C>G	p.Phe143Leu	missense_variant	Exon 2 of 5	ENST00000335325.9	NP_115644.1
ZNRF1	XM_017023793.2	c.429C>G	p.Phe143Leu	missense_variant	Exon 2 of 5		XP_016879282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNRF1	ENST00000335325.9	c.429C>G	p.Phe143Leu	missense_variant	Exon 2 of 5	1	NM_032268.5	ENSP00000335091.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.429C>G (p.F143L) alteration is located in exon 2 (coding exon 2) of the ZNRF1 gene. This alteration results from a C to G substitution at nucleotide position 429, causing the phenylalanine (F) at amino acid position 143 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;L
PhyloP100		3.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.091
Sift	Benign	0.58	T;T;T;T
Sift4G	Benign	0.14	T;T;D;T
Polyphen		0.064	B;B;.;B
Vest4		0.51
MutPred		0.40		Gain of disorder (P = 0.1843);Gain of disorder (P = 0.1843);Gain of disorder (P = 0.1843);Gain of disorder (P = 0.1843);
MVP		0.082
MPC		0.78
ClinPred		0.87	D
GERP RS		5.0
Varity_R		0.62
gMVP		0.84

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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Other links and lift over

dbSNP: rs2036166043; hg19: chr16-75127474;