chr8-103318590-C-G

Variant names:

• chr8-103318590-C-G
• rs780099524
• NM_003506.4:c.178C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003506.4(FZD6):​c.178C>G​(p.His60Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000141 in 1,418,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. H60Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FZD6 NM_003506.4 missense, splice_region
• Scores: Splicing: ADA: 0.001559
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 0 publications found

Genes affected

FZD6 (HGNC:4044): (frizzled class receptor 6) This gene represents a member of the 'frizzled' gene family, which encode 7-transmembrane domain proteins that are receptors for Wnt signaling proteins. The protein encoded by this family member contains a signal peptide, a cysteine-rich domain in the N-terminal extracellular region, and seven transmembrane domains, but unlike other family members, this protein does not contain a C-terminal PDZ domain-binding motif. This protein functions as a negative regulator of the canonical Wnt/beta-catenin signaling cascade, thereby inhibiting the processes that trigger oncogenic transformation, cell proliferation, and inhibition of apoptosis. Alternative splicing results in multiple transcript variants, some of which do not encode a protein with a predicted signal peptide.[provided by RefSeq, Aug 2011]

BAALC-AS1 (HGNC:50461): (BAALC antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27699375).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003506.4. 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
	FZD6	NM_003506.4	MANE Select	c.178C>G	p.His60Asp	missense splice_region	Exon 3 of 7	NP_003497.2
	FZD6	NM_001164615.2		c.178C>G	p.His60Asp	missense splice_region	Exon 3 of 7	NP_001158087.1	O60353-1
	FZD6	NM_001164616.2		c.82C>G	p.His28Asp	missense splice_region	Exon 4 of 8	NP_001158088.1	O60353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD6	ENST00000358755.5	TSL:1 MANE Select	c.178C>G	p.His60Asp	missense splice_region	Exon 3 of 7	ENSP00000351605.4	O60353-1
	FZD6	ENST00000522566.5	TSL:1	c.178C>G	p.His60Asp	missense splice_region	Exon 3 of 7	ENSP00000429055.1	O60353-1
	FZD6	ENST00000522484.5	TSL:1	n.178C>G		splice_region non_coding_transcript_exon	Exon 3 of 6	ENSP00000428301.1	G5EA13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250774 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000141 AC: 2 AN: 1418706 Hom.: 0 Cov.: 27 AF XY: 0.00000282 AC XY: 2 AN XY: 708626

African (AFR) AF: 0.00 AC: 0 AN: 32628

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072888

Other (OTH) AF: 0.00 AC: 0 AN: 58840

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.016
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.32	N
PhyloP100		4.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.17
Sift	Benign	0.079	T
Sift4G	Benign	0.35	T
Polyphen		0.0020	B
Vest4		0.37
MutPred		0.49		Loss of catalytic residue at L62 (P = 0.0556)
MVP		0.92
MPC		0.35
ClinPred		0.35	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.84
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.19
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: rs780099524; hg19: chr8-104330818;