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GeneBe

7-37909680-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP7BS1_SupportingBS2

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

2
Splicing: ADA: 0.03078
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.274
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 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
BS2
High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SFRP4NM_003014.4 linkuse as main transcriptc.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
SFRP4ENST00000436072.7 linkuse as main transcriptc.792G>A p.Arg264= splice_region_variant, synonymous_variant 5/61 NM_003014.4 P1
SFRP4ENST00000447200.2 linkuse as main transcriptc.390G>A p.Arg130= splice_region_variant, synonymous_variant 6/65
SFRP4ENST00000478975.1 linkuse as main transcriptn.160G>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.000612
AC:
93
AN:
151884
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 26, 2022This 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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