19-14397167-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_078481.4(ADGRE5):c.569C>T(p.Pro190Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.70

Genes affected

ADGRE5 (HGNC:1711): (adhesion G protein-coupled receptor E5) This gene encodes a member of the EGF-TM7 subfamily of adhesion G protein-coupled receptors, which mediate cell-cell interactions. These proteins are cleaved by self-catalytic proteolysis into a large extracellular subunit and seven-span transmembrane subunit, which associate at the cell surface as a receptor complex. The encoded protein may play a role in cell adhesion as well as leukocyte recruitment, activation and migration, and contains multiple extracellular EGF-like repeats which mediate binding to chondroitin sulfate and the cell surface complement regulatory protein CD55. Expression of this gene may play a role in the progression of several types of cancer. Alternatively spliced transcript variants encoding multiple isoforms with 3 to 5 EGF-like repeats have been observed for this gene. This gene is found in a cluster with other EGF-TM7 genes on the short arm of chromosome 19. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32369953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE5	NM_078481.4	c.569C>T	p.Pro190Leu	missense_variant	6/20	ENST00000242786.6
ADGRE5	NM_001025160.3	c.479-491C>T		intron_variant
ADGRE5	NM_001784.6	c.347-491C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE5	ENST00000242786.6	c.569C>T	p.Pro190Leu	missense_variant	6/20	1	NM_078481.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251416 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000330 AC: 4

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

Feb 27, 2023

The c.569C>T (p.P190L) alteration is located in exon 6 (coding exon 6) of the ADGRE5 gene. This alteration results from a C to T substitution at nucleotide position 569, causing the proline (P) at amino acid position 190 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	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	10
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.69	T;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
Sift4G	Benign	0.13	T;T
Vest4		0.32
MutPred		0.50		.;Gain of catalytic residue at P190 (P = 0.0043);
MVP		0.43
MPC		1.4
ClinPred		0.12	T
GERP RS		-0.23
gMVP		0.82

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: rs568383810; hg19: chr19-14507979; COSMIC: COSV54410623; COSMIC: COSV54410623;