rs461645

Positions:

• chr19-6919742-A-G
• chr19-6919742-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001974.5(ADGRE1):​c.1615A>G​(p.Ile539Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 1,612,378 control chromosomes in the GnomAD database, including 492,849 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.73 (41427 hom., cov: 28)
  • Exomes 𝑓: 0.79 (451422 hom.)
• Consequence: ADGRE1 NM_001974.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0770

Genes affected

ADGRE1 (HGNC:3336): (adhesion G protein-coupled receptor E1) This gene encodes a protein that has a domain resembling seven transmembrane G protein-coupled hormone receptors (7TM receptors) at its C-terminus. The N-terminus of the encoded protein has six EGF-like modules, separated from the transmembrane segments by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

LOC105372256 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.3166597E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRE1	NM_001974.5	c.1615A>G	p.Ile539Val	missense_variant	13/21	ENST00000312053.9	NP_001965.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRE1	ENST00000312053.9	c.1615A>G	p.Ile539Val	missense_variant	13/21	1	NM_001974.5	ENSP00000311545.3

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111172 AN: 151422 Hom.: 41408 Cov.: 28

Gnomad AFR AF: 0.608

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.792

Gnomad SAS AF: 0.759

Gnomad FIN AF: 0.803

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.784

Gnomad OTH AF: 0.729

GnomAD3 exomes AF: 0.771 AC: 193180 AN: 250662 Hom.: 74814 AF XY: 0.771 AC XY: 104559 AN XY: 135538

Gnomad AFR exome AF: 0.603

Gnomad AMR exome AF: 0.802

Gnomad ASJ exome AF: 0.758

Gnomad EAS exome AF: 0.784

Gnomad SAS exome AF: 0.763

Gnomad FIN exome AF: 0.806

Gnomad NFE exome AF: 0.781

Gnomad OTH exome AF: 0.747

GnomAD4 exome AF: 0.785 AC: 1146827 AN: 1460838 Hom.: 451422 Cov.: 42 AF XY: 0.784 AC XY: 569848 AN XY: 726716

Gnomad4 AFR exome AF: 0.590

Gnomad4 AMR exome AF: 0.797

Gnomad4 ASJ exome AF: 0.756

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.769

Gnomad4 FIN exome AF: 0.803

Gnomad4 NFE exome AF: 0.792

Gnomad4 OTH exome AF: 0.762

GnomAD4 genome AF: 0.734 AC: 111232 AN: 151540 Hom.: 41427 Cov.: 28 AF XY: 0.736 AC XY: 54440 AN XY: 73986

Gnomad4 AFR AF: 0.608

Gnomad4 AMR AF: 0.774

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.791

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.803

Gnomad4 NFE AF: 0.784

Gnomad4 OTH AF: 0.722

Alfa AF: 0.773 Hom.: 94085

Bravo AF: 0.727

TwinsUK AF: 0.801 AC: 2969

ALSPAC AF: 0.798 AC: 3076

ESP6500AA AF: 0.606 AC: 2671

ESP6500EA AF: 0.788 AC: 6774

ExAC AF: 0.764 AC: 92805

Asia WGS AF: 0.661 AC: 2301 AN: 3478

EpiCase AF: 0.763

EpiControl AF: 0.772

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.060	.;.;T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.56	T;T;T;T;T
MetaRNN	Benign	9.3e-7	T;T;T;T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.30	N;N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.81	T;T;T;T;T
Sift4G	Benign	0.67	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.13
MPC		0.20
ClinPred		0.0035	T
GERP RS		-0.14
Varity_R		0.069
gMVP		0.042

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs461645; hg19: chr19-6919753; COSMIC: COSV51673594;