7-37909673-G-A

Variant names:

• chr7-37909673-G-A
• rs751834775
• NM_003014.4:c.799C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003014.4(SFRP4):​c.799C>T​(p.Leu267Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,417,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SFRP4 NM_003014.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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]

ENSG00000290149 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFRP4	NM_003014.4	c.799C>T	p.Leu267Phe	missense_variant	Exon 5 of 6	ENST00000436072.7	NP_003005.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFRP4	ENST00000436072.7	c.799C>T	p.Leu267Phe	missense_variant	Exon 5 of 6	1	NM_003014.4	ENSP00000410715.2
ENSG00000290149	ENST00000476620.1	c.-37-39167G>A		intron_variant	Intron 2 of 3	4		ENSP00000425858.1
SFRP4	ENST00000447200.2	c.397C>T	p.Leu133Phe	missense_variant	Exon 6 of 6	5		ENSP00000402262.2
SFRP4	ENST00000478975.1	n.167C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 232664 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1417778 Hom.: 0 Cov.: 24 AF XY: 0.00000284 AC XY: 2 AN XY: 705224

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31842

Gnomad4 AMR exome AF: 0.0000246 AC: 1 AN: 40656

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25480

Gnomad4 EAS exome AF: 0.0000263 AC: 1 AN: 38066

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79238

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52824

Gnomad4 NFE exome AF: 9.21e-7 AC: 1 AN: 1085512

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 58526

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1416799). This variant has not been reported in the literature in individuals affected with SFRP4-related conditions. This variant is present in population databases (rs751834775, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 267 of the SFRP4 protein (p.Leu267Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.0	N;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.74		Gain of sheet (P = 0.0827);.;
MVP		0.87
MPC		1.2
ClinPred		0.91	D
GERP RS		6.0
Varity_R		0.53
gMVP		0.58
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs751834775; hg19: chr7-37949275;