rs921186769

Variant names:

• chr2-207767089-T-C
• rs921186769
• NM_003468.4:c.1651A>G

Variant summary

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

The NM_003468.4(FZD5):​c.1651A>G​(p.Met551Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,848 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FZD5 NM_003468.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.209
• Publications: 0 publications found

Genes affected

FZD5 (HGNC:4043): (frizzled class receptor 5) Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD5 protein is believed to be the receptor for the Wnt5A ligand. [provided by RefSeq, Jul 2008]

FZD5 Gene-Disease associations (from GenCC):

• microphthalmia/coloboma 11

  Inheritance: AD Classification: STRONG Submitted by: G2P

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=0.049590707).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003468.4. 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
	FZD5	NM_003468.4	MANE Select	c.1651A>G	p.Met551Val	missense	Exon 2 of 2	NP_003459.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD5	ENST00000295417.4	TSL:1 MANE Select	c.1651A>G	p.Met551Val	missense	Exon 2 of 2	ENSP00000354607.3	Q13467
	FZD5	ENST00000908573.1		c.1651A>G	p.Met551Val	missense	Exon 2 of 2	ENSP00000578632.1
	FZD5	ENST00000937374.1		c.1651A>G	p.Met551Val	missense	Exon 2 of 2	ENSP00000607433.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000487 AC: 1 AN: 205298 AF XY: 0.00000880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439848 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 714750

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.0000236 AC: 1 AN: 42338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 83998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5566

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102464

Other (OTH) AF: 0.00 AC: 0 AN: 59486

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.3
DANN	Benign	0.63
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.21
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.15
Sift	Benign	0.71	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.023
MutPred		0.25		Loss of MoRF binding (P = 0.11)
MVP		0.26
ClinPred		0.065	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.38
Mutation Taster		=96/4	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: rs921186769; hg19: chr2-208631813;