19-14401510-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_078481.4(ADGRE5):c.1022T>G(p.Leu341Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE5	NM_078481.4	c.1022T>G	p.Leu341Arg	missense_variant	10/20	ENST00000242786.6
ADGRE5	NM_001025160.3	c.875T>G	p.Leu292Arg	missense_variant	9/19
ADGRE5	NM_001784.6	c.743T>G	p.Leu248Arg	missense_variant	8/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE5	ENST00000242786.6	c.1022T>G	p.Leu341Arg	missense_variant	10/20	1	NM_078481.4	P1
ADGRE5	ENST00000357355.7	c.875T>G	p.Leu292Arg	missense_variant	9/19	1
ADGRE5	ENST00000358600.7	c.743T>G	p.Leu248Arg	missense_variant	8/18	1
ADGRE5	ENST00000586849.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

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

Sep 19, 2022

The c.1022T>G (p.L341R) alteration is located in exon 10 (coding exon 10) of the ADGRE5 gene. This alteration results from a T to G substitution at nucleotide position 1022, causing the leucine (L) at amino acid position 341 to be replaced by an arginine (R). 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	0.32
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Vest4		0.75
MutPred		0.54		.;.;Loss of stability (P = 0.0469);
MVP		0.78
MPC		0.72
ClinPred		0.99	D
GERP RS		5.5
gMVP		0.80

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: rs1043275920; hg19: chr19-14512322;