rs80358281

Variant names:

• chr11-86954979-C-G
• NM_012193.4:c.107G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-86954979-C-G
• chr11-86954979-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_012193.4(FZD4):​c.107G>C​(p.Gly36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. G36D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FZD4 NM_012193.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27

Genes affected

FZD4 (HGNC:4042): (frizzled class receptor 4) This gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the Wingless type MMTV integration site family of signaling proteins. Most frizzled receptors are coupled to the beta-catenin canonical signaling pathway. This protein may play a role as a positive regulator of the Wingless type MMTV integration site signaling pathway. A transcript variant retaining intronic sequence and encoding a shorter isoform has been described, however, its expression is not supported by other experimental evidence. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a signal_peptide (size 35) in uniprot entity FZD4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_012193.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16976482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD4	NM_012193.4	c.107G>C	p.Gly36Ala	missense_variant	Exon 1 of 2	ENST00000531380.2	NP_036325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD4	ENST00000531380.2	c.107G>C	p.Gly36Ala	missense_variant	Exon 1 of 2	1	NM_012193.4	ENSP00000434034.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.37		Loss of disorder (P = 0.1052);
MVP		0.53
MPC		0.30
ClinPred		0.27	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-86666021;