chr19-14397739-G-A

Variant names:

• chr19-14397739-G-A
• rs758717825
• NM_078481.4:c.707G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_078481.4(ADGRE5):​c.707G>A​(p.Arg236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,291,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 18)
  • Exomes 𝑓: 0.000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRE5 NM_078481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.20
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16643223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRE5	NM_078481.4	MANE Select	c.707G>A	p.Arg236His	missense	Exon 7 of 20	NP_510966.1	P48960-1
	ADGRE5	NM_001025160.3		c.560G>A	p.Arg187His	missense	Exon 6 of 19	NP_001020331.1	P48960-3
	ADGRE5	NM_001784.6		c.428G>A	p.Arg143His	missense	Exon 5 of 18	NP_001775.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRE5	ENST00000242786.6	TSL:1 MANE Select	c.707G>A	p.Arg236His	missense	Exon 7 of 20	ENSP00000242786.4	P48960-1
	ADGRE5	ENST00000357355.7	TSL:1	c.560G>A	p.Arg187His	missense	Exon 6 of 19	ENSP00000349918.2	P48960-3
	ADGRE5	ENST00000358600.7	TSL:1	c.428G>A	p.Arg143His	missense	Exon 5 of 18	ENSP00000351413.2	P48960-2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 129660 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000969 AC: 2 AN: 206390 AF XY: 0.00000882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 18 AN: 1291604 Hom.: 0 Cov.: 22 AF XY: 0.0000154 AC XY: 10 AN XY: 647808

African (AFR) AF: 0.00 AC: 0 AN: 29612

American (AMR) AF: 0.0000469 AC: 2 AN: 42632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24864

East Asian (EAS) AF: 0.00 AC: 0 AN: 38306

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4668

European-Non Finnish (NFE) AF: 0.0000156 AC: 15 AN: 963686

Other (OTH) AF: 0.00 AC: 0 AN: 54398

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 129660 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 61674

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 11940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 4528

South Asian (SAS) AF: 0.00 AC: 0 AN: 3746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62130

Other (OTH) AF: 0.00 AC: 0 AN: 1744

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	3.2
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.55	T
PhyloP100		-3.2
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.51	T
Sift4G	Benign	0.65	T
Vest4		0.10
MutPred		0.57		Loss of MoRF binding (P = 0.0708)
MVP		0.23
MPC		2.2
ClinPred		0.055	T
GERP RS		-4.2
gMVP		0.45
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs758717825; hg19: chr19-14508551;