rs1802074

Positions:

• chr7-37907501-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003014.4(SFRP4):​c.1019G>A​(p.Arg340Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,611,698 control chromosomes in the GnomAD database, including 36,456 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (4872 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31584 hom.)
• Consequence: SFRP4 NM_003014.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.695

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003261745).
• BP6: Variant 7-37907501-C-T is Benign according to our data. Variant chr7-37907501-C-T is described in ClinVar as [Benign]. Clinvar id is 1332946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFRP4	NM_003014.4	c.1019G>A	p.Arg340Lys	missense_variant	6/6	ENST00000436072.7	NP_003005.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFRP4	ENST00000436072.7	c.1019G>A	p.Arg340Lys	missense_variant	6/6	1	NM_003014.4	ENSP00000410715	P1
SFRP4	ENST00000478975.1	n.387G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36804 AN: 151968 Hom.: 4866 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.198 AC: 49610 AN: 250532 Hom.: 5515 AF XY: 0.196 AC XY: 26499 AN XY: 135420

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.246

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.204 AC: 298058 AN: 1459612 Hom.: 31584 Cov.: 32 AF XY: 0.203 AC XY: 147216 AN XY: 726192

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.218

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.242 AC: 36839 AN: 152086 Hom.: 4872 Cov.: 32 AF XY: 0.241 AC XY: 17894 AN XY: 74324

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.246

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.236

Alfa AF: 0.210 Hom.: 7415

Bravo AF: 0.240

TwinsUK AF: 0.212 AC: 786

ALSPAC AF: 0.210 AC: 810

ESP6500AA AF: 0.341 AC: 1503

ESP6500EA AF: 0.192 AC: 1651

ExAC AF: 0.203 AC: 24597

Asia WGS AF: 0.175 AC: 608 AN: 3478

EpiCase AF: 0.211

EpiControl AF: 0.210

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyle metaphyseal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

SFRP4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.3
DANN	Benign	0.72
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.086
Sift	Benign	0.86	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.38
ClinPred		0.000014	T
GERP RS		0.88
Varity_R		0.031
gMVP		0.13

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

Other links and lift over

dbSNP: rs1802074; hg19: chr7-37947103; COSMIC: COSV71412323; COSMIC: COSV71412323;