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GeneBe

7-37909618-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003014.4(SFRP4):c.854T>C(p.Ile285Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,399,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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: not found (cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SFRP4
NM_003014.4 missense, splice_region

Scores

1
18
Splicing: ADA: 0.0006433
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.56
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.105879396).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SFRP4NM_003014.4 linkuse as main transcriptc.854T>C p.Ile285Thr missense_variant, splice_region_variant 5/6 ENST00000436072.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SFRP4ENST00000436072.7 linkuse as main transcriptc.854T>C p.Ile285Thr missense_variant, splice_region_variant 5/61 NM_003014.4 P1
SFRP4ENST00000478975.1 linkuse as main transcriptn.222T>C splice_region_variant, non_coding_transcript_exon_variant 1/22
SFRP4ENST00000447200.2 linkuse as main transcript downstream_gene_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000136
AC:
19
AN:
1399688
Hom.:
0
Cov.:
24
AF XY:
0.0000158
AC XY:
11
AN XY:
696848
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000177
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 testingInvitaeAug 06, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with SFRP4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 285 of the SFRP4 protein (p.Ile285Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
19
DANN
Benign
0.94
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.68
T
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.90
N
REVEL
Benign
0.047
Sift
Benign
0.23
T
Sift4G
Benign
0.12
T
Polyphen
0.0
B
Vest4
0.23
MutPred
0.41
Loss of stability (P = 0.0406);
MVP
0.51
MPC
0.47
ClinPred
0.38
T
GERP RS
3.0
Varity_R
0.062
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00064
dbscSNV1_RF
Benign
0.014
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-37949220; API