chr10-97767849-G-A

Variant names:

• chr10-97767849-G-A
• rs748205313
• NM_003015.3:c.619C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003015.3(SFRP5):​c.619C>T​(p.Arg207Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000525 in 1,524,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: SFRP5 NM_003015.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44
• Publications: 8 publications found

Genes affected

SFRP5 (HGNC:10779): (secreted frizzled related protein 5) Secreted frizzled-related protein 5 (SFRP5) 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. SFRP5 and SFRP1 may be involved in determining the polarity of photoreceptor cells in the retina. SFRP5 is highly expressed in the retinal pigment epithelium, and moderately expressed in the pancreas. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34480077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003015.3. 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
	SFRP5	NM_003015.3	MANE Select	c.619C>T	p.Arg207Cys	missense	Exon 3 of 3	NP_003006.2	Q5T4F7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFRP5	ENST00000266066.4	TSL:1 MANE Select	c.619C>T	p.Arg207Cys	missense	Exon 3 of 3	ENSP00000266066.3	Q5T4F7

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 176160 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000437 AC: 6 AN: 1372342 Hom.: 0 Cov.: 31 AF XY: 0.00000594 AC XY: 4 AN XY: 673802

African (AFR) AF: 0.00 AC: 0 AN: 30324

American (AMR) AF: 0.00 AC: 0 AN: 29678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20056

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 39006

South Asian (SAS) AF: 0.0000284 AC: 2 AN: 70438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5324

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1071072

Other (OTH) AF: 0.00 AC: 0 AN: 56502

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

African (AFR) AF: 0.0000483 AC: 2 AN: 41392

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.21
Sift	Benign	0.079	T
Sift4G	Benign	0.085	T
Polyphen		0.81	P
Vest4		0.41
MutPred		0.55		Loss of MoRF binding (P = 0.011)
MVP		0.58
MPC		1.7
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.36
gMVP		0.70
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs748205313; hg19: chr10-99527606; COSMIC: COSV56604010;