rs879253778

Variant names:

• chr7-37914411-TCCTGTAC-T
• rs879253778
• NM_003014.4:c.481_487delGTACAGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003014.4(SFRP4):​c.481_487delGTACAGG​(p.Val161LysfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SFRP4 NM_003014.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.63
• 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: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-37914411-TCCTGTAC-T is Pathogenic according to our data. Variant chr7-37914411-TCCTGTAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 242997.Status of the report is criteria_provided_single_submitter, 1 stars.

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.481_487delGTACAGG	p.Val161LysfsTer11	frameshift	Exon 2 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.481_487delGTACAGG	p.Val161LysfsTer11	frameshift	Exon 2 of 6	ENSP00000410715.2	Q6FHJ7
	ENSG00000290149	ENST00000476620.1	TSL:4	c.-37-34427_-37-34421delCTGTACC		intron	N/A	ENSP00000425858.1	D6RIH7
	SFRP4	ENST00000960684.1		c.481_487delGTACAGG	p.Val161LysfsTer11	frameshift	Exon 2 of 6	ENSP00000630743.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Pyle metaphyseal dysplasia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.6
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs879253778;

hg19: chr7-37954013;