Genetic Variant SFRP1:p.Pro45Arg (chr8-41309026-G-C) – 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.134C>G(p.Pro45Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SFRP1
NM_003012.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

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=0.2285592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFRP1	NM_003012.5 link	c.134C>G	p.Pro45Arg	missense_variant	Exon 1 of 3	ENST00000220772.8	NP_003003.3	Q8N474

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFRP1	ENST00000220772.8 link	c.134C>G	p.Pro45Arg	missense_variant	Exon 1 of 3	1	NM_003012.5	ENSP00000220772.3		Q8N474

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245136

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457756

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725462

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33474

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44712

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26122

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39684

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86240

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

49554

Gnomad4 NFE exome

AF:

0.00000180

AC:

AN:

1111862

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60340

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.134C>G (p.P45R) alteration is located in exon 1 (coding exon 1) of the SFRP1 gene. This alteration results from a C to G substitution at nucleotide position 134, causing the proline (P) at amino acid position 45 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.67

REVEL

Benign

0.048

Sift

Benign

0.10

Sift4G

Uncertain

0.050

Polyphen

0.0040

Vest4

0.11

MutPred

0.44

Gain of methylation at P45 (P = 0.0431);

MVP

0.58

MPC

0.55

ClinPred

0.11

GERP RS

3.6

Varity_R

0.048

gMVP

0.46

Mutation Taster

=98/2

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

Publications

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over