rs72963441

Variant names:

• chr11-86946377-A-G
• rs72963441
• NM_012193.4:c.*4765T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012193.4(FZD4):​c.*4765T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 152,318 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (140 hom., cov: 32)
  • Exomes 𝑓: 0.079 (0 hom.)
• Consequence: FZD4 NM_012193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.94
• Publications: 6 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=-0.66).
• BP6: Variant 11-86946377-A-G is Benign according to our data. Variant chr11-86946377-A-G is described in ClinVar as Benign. ClinVar VariationId is 306333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

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.*4765T>C		3_prime_UTR	Exon 2 of 2	NP_036325.2
	PRSS23	NR_120591.3		n.435-3979A>G		intron	N/A
	PRSS23	NR_120592.2		n.328-4839A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FZD4	ENST00000531380.2	TSL:1 MANE Select	c.*4765T>C		3_prime_UTR	Exon 2 of 2	ENSP00000434034.1	Q9ULV1
	PRSS23	ENST00000532234.5	TSL:1	n.*65-3979A>G		intron	N/A	ENSP00000436676.1	E9PIB7
	PRSS23	ENST00000533902.2	TSL:4	c.207-4839A>G		intron	N/A	ENSP00000437268.1	E9PMX2

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5592 AN: 152162 Hom.: 140 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0596

Gnomad OTH AF: 0.0235

GnomAD4 exome AF: 0.0789 AC: 3 AN: 38 Hom.: 0 Cov.: 0 AF XY: 0.0938 AC XY: 3 AN XY: 32

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0938 AC: 3 AN: 32

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0367 AC: 5593 AN: 152280 Hom.: 140 Cov.: 32 AF XY: 0.0355 AC XY: 2647 AN XY: 74462

African (AFR) AF: 0.0108 AC: 451 AN: 41568

American (AMR) AF: 0.0272 AC: 416 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4824

European-Finnish (FIN) AF: 0.0421 AC: 447 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0596 AC: 4052 AN: 68010

Other (OTH) AF: 0.0232 AC: 49 AN: 2110

Alfa AF: 0.0458 Hom.: 74

Bravo AF: 0.0336

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

ClinVar submissions

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	-0.66
CADD	Benign	15
DANN	Benign	0.88
PhyloP100		1.9
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: rs72963441; hg19: chr11-86657419;