Genetic Variant SFRP1:p.Val312Leu (chr8-41265178-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003012.5(SFRP1):c.934G>T(p.Val312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000848 in 1,178,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V312M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Consequence

SFRP1
NM_003012.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.52

Publications

0 publications found

Variant links:

Genes affected

SFRP1 (HGNC:10776): (secreted frizzled related protein 1) This gene encodes a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. Members of this family act as soluble modulators of Wnt signaling; epigenetic silencing of SFRP genes leads to deregulated activation of the Wnt-pathway which is associated with cancer. This gene may also be involved in determining the polarity of photoreceptor cells in the retina. [provided by RefSeq, Sep 2009]

SFRP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18490297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003012.5. 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
	SFRP1	NM_003012.5	MANE Select	c.934G>T	p.Val312Leu	missense	Exon 3 of 3	NP_003003.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SFRP1	ENST00000220772.8	TSL:1 MANE Select	c.934G>T	p.Val312Leu	missense	Exon 3 of 3	ENSP00000220772.3	Q8N474
SFRP1	ENST00000923189.1		c.856G>T	p.Val286Leu	missense	Exon 2 of 2	ENSP00000593248.1
SFRP1	ENST00000379845.3	TSL:2	c.526G>T	p.Val176Leu	missense	Exon 3 of 3	ENSP00000369174.3	Q6ZSL4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.48e-7

AC:

AN:

1178692

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

582390

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25468

American (AMR)

AF:

0.00

AC:

AN:

35158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16306

East Asian (EAS)

AF:

0.00

AC:

AN:

15790

South Asian (SAS)

AF:

0.00

AC:

AN:

80038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

927872

Other (OTH)

AF:

0.0000236

AC:

AN:

42462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

M_CAP

Benign

0.029

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

PhyloP100

2.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.79

REVEL

Benign

0.071

Sift

Benign

0.17

Sift4G

Benign

0.14

Polyphen

0.053

Vest4

0.049

MutPred

0.17

Gain of helix (P = 0.0854)

MVP

0.73

MPC

0.50

ClinPred

0.54

GERP RS

4.9

Varity_R

0.11

gMVP

0.70

Mutation Taster

=81/19

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over