Genetic Variant EPDR1:p.Arg75Cys (chr7-37921162-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017549.5(EPDR1):c.223C>T(p.Arg75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,418 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EPDR1
NM_017549.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.95

Variant links:

Genes affected

EPDR1 (HGNC:17572): (ependymin related 1) The protein encoded by this gene is a type II transmembrane protein that is similar to two families of cell adhesion molecules, the protocadherins and ependymins. This protein may play a role in calcium-dependent cell adhesion. This protein is glycosylated, and the orthologous mouse protein is localized to the lysosome. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 8. [provided by RefSeq, Aug 2011]

EPDR1 links:

ENSG00000290149 (HGNC:):

ENSG00000290149 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPDR1	NM_017549.5 link	c.223C>T	p.Arg75Cys	missense_variant	Exon 1 of 3	ENST00000199448.9	NP_060019.2	Q9UM22-1Q96J80
EPDR1	NM_001242946.2 link	c.223C>T	p.Arg75Cys	missense_variant	Exon 1 of 2		NP_001229875.2	Q9UM22-2Q96J80
EPDR1	NM_001242948.2 link	c.-204C>T		upstream_gene_variant			NP_001229877.1	Q9UM22-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPDR1	ENST00000199448.9 link	c.223C>T	p.Arg75Cys	missense_variant	Exon 1 of 3	1	NM_017549.5	ENSP00000199448.4		Q9UM22-1
ENSG00000290149	ENST00000476620.1 link	c.-37-27678C>T		intron_variant	Intron 2 of 3	4		ENSP00000425858.1		D6RIH7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442418

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

0.040

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.62

MVP

0.25

MPC

0.33

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over