7-37948932-C-T

Position:

• chr7-37948932-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017549.5(EPDR1):​c.362C>T​(p.Pro121Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000677 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: EPDR1 NM_017549.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

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]

ENSG00000290149 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07825348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPDR1	NM_017549.5	c.362C>T	p.Pro121Leu	missense_variant	2/3	ENST00000199448.9	NP_060019.2
EPDR1	NM_001242948.2	c.179C>T	p.Pro60Leu	missense_variant	2/3		NP_001229877.1
EPDR1	NM_001242946.2	c.270-1268C>T		intron_variant			NP_001229875.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPDR1	ENST00000199448.9	c.362C>T	p.Pro121Leu	missense_variant	2/3	1	NM_017549.5	ENSP00000199448.4
ENSG00000290149	ENST00000476620.1	c.56C>T	p.Pro19Leu	missense_variant	3/4	4		ENSP00000425858.1

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000378 AC: 95 AN: 251388 Hom.: 0 AF XY: 0.000398 AC XY: 54 AN XY: 135844

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000697 AC: 1019 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.000689 AC XY: 501 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000883

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74384

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000799 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

The c.362C>T (p.P121L) alteration is located in exon 2 (coding exon 2) of the EPDR1 gene. This alteration results from a C to T substitution at nucleotide position 362, causing the proline (P) at amino acid position 121 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.2	.;M;.
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Vest4		0.33
MVP		0.17
MPC		0.33
ClinPred		0.47	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs149095633; hg19: chr7-37988534;