rs373533

Variant names:

• chr19-6919613-A-C
• rs373533
• NM_001974.5:c.1486A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001974.5(ADGRE1):​c.1486A>C​(p.Lys496Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 1,612,790 control chromosomes in the GnomAD database, including 496,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.74 (41520 hom., cov: 26)
  • Exomes 𝑓: 0.79 (455020 hom.)
• Consequence: ADGRE1 NM_001974.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.903
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2113865E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001974.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRE1	NM_001974.5	MANE Select	c.1486A>C	p.Lys496Gln	missense	Exon 13 of 21	NP_001965.3
	ADGRE1	NM_001256252.2		c.1330A>C	p.Lys444Gln	missense	Exon 12 of 20	NP_001243181.1
	ADGRE1	NM_001256253.2		c.1486A>C	p.Lys496Gln	missense	Exon 13 of 20	NP_001243182.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRE1	ENST00000312053.9	TSL:1 MANE Select	c.1486A>C	p.Lys496Gln	missense	Exon 13 of 21	ENSP00000311545.3
	ADGRE1	ENST00000250572.12	TSL:1	c.1486A>C	p.Lys496Gln	missense	Exon 13 of 20	ENSP00000250572.7
	ADGRE1	ENST00000381404.8	TSL:2	c.1330A>C	p.Lys444Gln	missense	Exon 12 of 20	ENSP00000370811.4

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111080 AN: 150830 Hom.: 41500 Cov.: 26

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.795

Gnomad SAS AF: 0.767

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.734

GnomAD2 exomes AF: 0.774 AC: 194692 AN: 251446 AF XY: 0.775

Gnomad AFR exome AF: 0.604

Gnomad AMR exome AF: 0.806

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.807

Gnomad NFE exome AF: 0.783

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.788 AC: 1151819 AN: 1461842 Hom.: 455020 Cov.: 65 AF XY: 0.787 AC XY: 572461 AN XY: 727226

African (AFR) AF: 0.592 AC: 19814 AN: 33478

American (AMR) AF: 0.801 AC: 35818 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 19943 AN: 26130

East Asian (EAS) AF: 0.813 AC: 32281 AN: 39700

South Asian (SAS) AF: 0.780 AC: 67252 AN: 86256

European-Finnish (FIN) AF: 0.804 AC: 42929 AN: 53412

Middle Eastern (MID) AF: 0.686 AC: 3951 AN: 5762

European-Non Finnish (NFE) AF: 0.795 AC: 883639 AN: 1111990

Other (OTH) AF: 0.765 AC: 46192 AN: 60390

GnomAD4 genome AF: 0.736 AC: 111140 AN: 150948 Hom.: 41520 Cov.: 26 AF XY: 0.738 AC XY: 54333 AN XY: 73636

African (AFR) AF: 0.609 AC: 24966 AN: 41002

American (AMR) AF: 0.776 AC: 11710 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2671 AN: 3466

East Asian (EAS) AF: 0.794 AC: 4027 AN: 5072

South Asian (SAS) AF: 0.768 AC: 3651 AN: 4754

European-Finnish (FIN) AF: 0.804 AC: 8376 AN: 10422

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.786 AC: 53341 AN: 67834

Other (OTH) AF: 0.727 AC: 1525 AN: 2098

Alfa AF: 0.768 Hom.: 176885

Bravo AF: 0.728

TwinsUK AF: 0.803 AC: 2977

ALSPAC AF: 0.800 AC: 3085

ESP6500AA AF: 0.608 AC: 2680

ESP6500EA AF: 0.790 AC: 6792

ExAC AF: 0.768 AC: 93262

Asia WGS AF: 0.671 AC: 2333 AN: 3478

EpiCase AF: 0.765

EpiControl AF: 0.774

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.81
DANN	Benign	0.094
DEOGEN2	Benign	0.041	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00096	N
LIST_S2	Benign	0.089	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.90
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.067
Sift	Benign	0.45	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.13
MPC		0.10
ClinPred		0.0010	T
GERP RS		0.50
Varity_R		0.040
gMVP		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs373533; hg19: chr19-6919624; COSMIC: COSV51673014;