chr19-14397745-G-A

Position:

• chr19-14397745-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_078481.4(ADGRE5):​c.713G>A​(p.Arg238His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,408,374 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.00014 (0 hom., cov: 18)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.21

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050213426).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE5	NM_078481.4	c.713G>A	p.Arg238His	missense_variant	7/20	ENST00000242786.6
ADGRE5	NM_001025160.3	c.566G>A	p.Arg189His	missense_variant	6/19
ADGRE5	NM_001784.6	c.434G>A	p.Arg145His	missense_variant	5/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE5	ENST00000242786.6	c.713G>A	p.Arg238His	missense_variant	7/20	1	NM_078481.4	P1

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 18 AN: 127514 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000123

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: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000212

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000296 AC: 59 AN: 199270 Hom.: 0 AF XY: 0.000357 AC XY: 39 AN XY: 109236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000713

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000655

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000284

Gnomad NFE exome AF: 0.000560

Gnomad OTH exome AF: 0.000394

GnomAD4 exome AF: 0.000326 AC: 417 AN: 1280762 Hom.: 3 Cov.: 22 AF XY: 0.000305 AC XY: 196 AN XY: 642456

Gnomad4 AFR exome AF: 0.000102

Gnomad4 AMR exome AF: 0.0000477

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000696

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.000204

GnomAD4 genome AF: 0.000141 AC: 18 AN: 127612 Hom.: 0 Cov.: 18 AF XY: 0.000132 AC XY: 8 AN XY: 60700

Gnomad4 AFR AF: 0.000123

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000129

Gnomad4 NFE AF: 0.000212

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000316 Hom.: 0

ExAC AF: 0.000455 AC: 54

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

Dec 16, 2022

The c.713G>A (p.R238H) alteration is located in exon 7 (coding exon 7) of the ADGRE5 gene. This alteration results from a G to A substitution at nucleotide position 713, causing the arginine (R) at amino acid position 238 to be replaced by a histidine (H). 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	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.050	T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D;.;D;D
REVEL	Benign	0.22
Sift	Benign	0.18	T;.;T;T
Sift4G	Benign	0.40	T;T;T;T
Vest4		0.17
MVP		0.56
MPC		2.2
ClinPred		0.089	T
GERP RS		-5.5
gMVP		0.75

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: rs548656990; hg19: chr19-14508557;