NM_003014.4:c.1019G>A

Variant names:

• chr7-37907501-C-T
• rs1802074
• NM_003014.4:c.1019G>A

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 45 publications found

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]

SFRP4 Gene-Disease associations (from GenCC):

• Pyle disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003014.4. 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
	SFRP4	NM_003014.4	MANE Select	c.1019G>A	p.Arg340Lys	missense	Exon 6 of 6	NP_003005.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFRP4	ENST00000436072.7	TSL:1 MANE Select	c.1019G>A	p.Arg340Lys	missense	Exon 6 of 6	ENSP00000410715.2
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-37-41339C>T		intron	N/A	ENSP00000425858.1
	SFRP4	ENST00000960684.1		c.1043G>A	p.Arg348Lys	missense	Exon 6 of 6	ENSP00000630743.1

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

GnomAD2 exomes AF: 0.198 AC: 49610 AN: 250532 AF XY: 0.196

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 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

African (AFR) AF: 0.346 AC: 11513 AN: 33292

American (AMR) AF: 0.105 AC: 4653 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 5689 AN: 26072

East Asian (EAS) AF: 0.240 AC: 9520 AN: 39676

South Asian (SAS) AF: 0.135 AC: 11583 AN: 86066

European-Finnish (FIN) AF: 0.244 AC: 13048 AN: 53388

Middle Eastern (MID) AF: 0.271 AC: 1555 AN: 5730

European-Non Finnish (NFE) AF: 0.205 AC: 228100 AN: 1110570

Other (OTH) AF: 0.206 AC: 12397 AN: 60314

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

African (AFR) AF: 0.347 AC: 14396 AN: 41462

American (AMR) AF: 0.161 AC: 2459 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 715 AN: 3472

East Asian (EAS) AF: 0.246 AC: 1271 AN: 5166

South Asian (SAS) AF: 0.130 AC: 628 AN: 4822

European-Finnish (FIN) AF: 0.259 AC: 2743 AN: 10584

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13884 AN: 67986

Other (OTH) AF: 0.236 AC: 497 AN: 2108

Alfa AF: 0.214 Hom.: 14811

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pyle metaphyseal dysplasia (1)
-	-	1	SFRP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.69
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
Mutation Taster		=96/4	polymorphism (auto)

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