7-37909680-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP7 BS1_Supporting

The NM_003014.4(SFRP4):c.792G>A(p.Arg264=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,562,410 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: SFRP4 NM_003014.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.03078
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.274

Genes affected

SFRP4 (HGNC:10778): (secreted frizzled related protein 4) Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP7: Synonymous conserved (PhyloP=0.274 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000612 (93/152000) while in subpopulation NFE AF= 0.000913 (62/67924). AF 95% confidence interval is 0.00073. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFRP4	NM_003014.4	c.792G>A	p.Arg264=	splice_region_variant, synonymous_variant	5/6	ENST00000436072.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFRP4	ENST00000436072.7	c.792G>A	p.Arg264=	splice_region_variant, synonymous_variant	5/6	1	NM_003014.4	P1
SFRP4	ENST00000447200.2	c.390G>A	p.Arg130=	splice_region_variant, synonymous_variant	6/6	5
SFRP4	ENST00000478975.1	n.160G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000913

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000718 AC: 165 AN: 229684 Hom.: 0 AF XY: 0.000755 AC XY: 94 AN XY: 124422

Gnomad AFR exome AF: 0.000334

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000860

Gnomad FIN exome AF: 0.000751

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000555

GnomAD4 exome AF: 0.00101 AC: 1422 AN: 1410410 Hom.: 4 Cov.: 23 AF XY: 0.000979 AC XY: 687 AN XY: 701878

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.000174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.00119

Gnomad4 NFE exome AF: 0.00113

Gnomad4 OTH exome AF: 0.000807

GnomAD4 genome AF: 0.000612 AC: 93 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74286

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.000948

Gnomad4 NFE AF: 0.000913

Gnomad4 OTH AF: 0.000952

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000665

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2022

This sequence change affects codon 264 of the SFRP4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SFRP4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs147388554, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SFRP4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1525259). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs147388554; hg19: chr7-37949282; COSMIC: COSV71412279;