rs138561450

Variant names:

• chr11-86946946-T-C
• rs138561450
• NM_012193.4:c.*4196A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012193.4(FZD4):​c.*4196A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 152,176 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FZD4 NM_012193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.14
• Publications: 2 publications found

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]

PRSS23 (HGNC:14370): (serine protease 23) This gene encodes a conserved member of the trypsin family of serine proteases. Mouse studies found a decrease of mRNA levels of this gene after ovulation was induced. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 11-86946946-T-C is Benign according to our data. Variant chr11-86946946-T-C is described in ClinVar as Benign. ClinVar VariationId is 306341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0161 (2448/152176) while in subpopulation SAS AF = 0.0264 (127/4812). AF 95% confidence interval is 0.0227. There are 25 homozygotes in GnomAd4. There are 1151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2448 SD,AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012193.4. 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
	FZD4	NM_012193.4	MANE Select	c.*4196A>G		3_prime_UTR	Exon 2 of 2	NP_036325.2
	PRSS23	NR_120591.3		n.435-3410T>C		intron	N/A
	PRSS23	NR_120592.2		n.328-4270T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD4	ENST00000531380.2	TSL:1 MANE Select	c.*4196A>G		3_prime_UTR	Exon 2 of 2	ENSP00000434034.1	Q9ULV1
	PRSS23	ENST00000532234.5	TSL:1	n.*65-3410T>C		intron	N/A	ENSP00000436676.1	E9PIB7
	PRSS23	ENST00000533902.2	TSL:4	c.207-4270T>C		intron	N/A	ENSP00000437268.1	E9PMX2

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2437 AN: 152058 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0266

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0148

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00325 AC: 1 AN: 308 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 234

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.00 AC: 0 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00410 AC: 1 AN: 244

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.0161 AC: 2448 AN: 152176 Hom.: 25 Cov.: 32 AF XY: 0.0155 AC XY: 1151 AN XY: 74400

African (AFR) AF: 0.0153 AC: 636 AN: 41524

American (AMR) AF: 0.0230 AC: 352 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0264 AC: 127 AN: 4812

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1201 AN: 67992

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0171 Hom.: 3

Bravo AF: 0.0180

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Exudative vitreoretinopathy 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs138561450; hg19: chr11-86657988; COSMIC: COSV73205731;