chr7-37909680-C-T

Variant names:

• chr7-37909680-C-T
• rs147388554
• NM_003014.4:c.792G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP7 BS1_Supporting BS2

The NM_003014.4(SFRP4):​c.792G>A​(p.Arg264Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,562,410 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: SFRP4 NM_003014.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.03078
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.274
• Publications: 3 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: Orphanet, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP7: Synonymous conserved (PhyloP=0.274 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000612 (93/152000) while in subpopulation NFE AF = 0.000913 (62/67924). AF 95% confidence interval is 0.00073. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.792G>A	p.Arg264Arg	splice_region synonymous	Exon 5 of 6	NP_003005.2	Q6FHJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFRP4	ENST00000436072.7	TSL:1 MANE Select	c.792G>A	p.Arg264Arg	splice_region synonymous	Exon 5 of 6	ENSP00000410715.2	Q6FHJ7
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-37-39160C>T		intron	N/A	ENSP00000425858.1	D6RIH7
	SFRP4	ENST00000960684.1		c.792G>A	p.Arg264Arg	splice_region synonymous	Exon 5 of 6	ENSP00000630743.1

Frequencies

GnomAD3 genomes AF: 0.000612 AC: 93 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000913

Gnomad OTH AF: 0.000962

GnomAD2 exomes AF: 0.000718 AC: 165 AN: 229684 AF XY: 0.000755

Gnomad AFR exome AF: 0.000334

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000751

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.000555

GnomAD4 exome AF: 0.00101 AC: 1422 AN: 1410410 Hom.: 4 Cov.: 23 AF XY: 0.000979 AC XY: 687 AN XY: 701878

African (AFR) AF: 0.0000949 AC: 3 AN: 31602

American (AMR) AF: 0.000174 AC: 7 AN: 40134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25324

East Asian (EAS) AF: 0.00 AC: 0 AN: 38058

South Asian (SAS) AF: 0.00107 AC: 84 AN: 78428

European-Finnish (FIN) AF: 0.00119 AC: 63 AN: 52822

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5600

European-Non Finnish (NFE) AF: 0.00113 AC: 1217 AN: 1080166

Other (OTH) AF: 0.000807 AC: 47 AN: 58276

GnomAD4 genome AF: 0.000612 AC: 93 AN: 152000 Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33 AN XY: 74286

African (AFR) AF: 0.000337 AC: 14 AN: 41504

American (AMR) AF: 0.000197 AC: 3 AN: 15262

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.000948 AC: 10 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000913 AC: 62 AN: 67924

Other (OTH) AF: 0.000952 AC: 2 AN: 2100

Alfa AF: 0.00109 Hom.: 2

Bravo AF: 0.000665

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.77
PhyloP100		0.27
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.13		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: rs147388554; hg19: chr7-37949282; COSMIC: COSV71412279;