rs770136662

Variant names:

• chr2-202035905-G-A
• rs770136662
• NM_003507.2:c.1258G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-202035905-G-A
• chr2-202035905-G-T

Variant summary

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

The NM_003507.2(FZD7):​c.1258G>A​(p.Ala420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A420S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FZD7 NM_003507.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 0 publications found

Genes affected

FZD7 (HGNC:4045): (frizzled class receptor 7) Members of the 'frizzled' gene family encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The FZD7 protein contains an N-terminal signal sequence, 10 cysteine residues typical of the cysteine-rich extracellular domain of Fz family members, 7 putative transmembrane domains, and an intracellular C-terminal tail with a PDZ domain-binding motif. FZD7 gene expression may downregulate APC function and enhance beta-catenin-mediated signals in poorly differentiated human esophageal carcinomas. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FZD7	NM_003507.2	c.1258G>A	p.Ala420Thr	missense_variant	Exon 1 of 1	ENST00000286201.3	NP_003498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FZD7	ENST00000286201.3	c.1258G>A	p.Ala420Thr	missense_variant	Exon 1 of 1	6	NM_003507.2	ENSP00000286201.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461692 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727162

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

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T
Sift4G	Benign	0.18	T
Polyphen		0.90	P
Vest4		0.27
MutPred		0.75		Loss of methylation at R422 (P = 0.1271);
MVP		0.78
MPC		1.3
ClinPred		0.90	D
GERP RS		5.5
Varity_R		0.22
gMVP		0.54
Mutation Taster		=76/24	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: rs770136662; hg19: chr2-202900628;