rs373533

chr19-6919613-A-C

Variant summary

Our verdict is Benign. Variant got -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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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=1.2113865E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE1	NM_001974.5	c.1486A>C	p.Lys496Gln	missense_variant	13/21	ENST00000312053.9
LOC105372256	XR_936288.4	n.64-7225T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE1	ENST00000312053.9	c.1486A>C	p.Lys496Gln	missense_variant	13/21	1	NM_001974.5	P1

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

GnomAD3 exomes AF: 0.774 AC: 194692 AN: 251446 Hom.: 75752 AF XY: 0.775 AC XY: 105374 AN XY: 135900

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 SAS exome AF: 0.774

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

Gnomad4 AFR exome AF: 0.592

Gnomad4 AMR exome AF: 0.801

Gnomad4 ASJ exome AF: 0.763

Gnomad4 EAS exome AF: 0.813

Gnomad4 SAS exome AF: 0.780

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.795

Gnomad4 OTH exome AF: 0.765

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

Gnomad4 AFR AF: 0.609

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.771

Gnomad4 EAS AF: 0.794

Gnomad4 SAS AF: 0.768

Gnomad4 FIN AF: 0.804

Gnomad4 NFE AF: 0.786

Gnomad4 OTH AF: 0.727

Alfa AF: 0.775 Hom.: 118595

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 v4.3

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00096	N
LIST_S2	Benign	0.089	T;T;T;T;T
MetaRNN	Benign	0.0000012	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Benign	0.067
Sift	Benign	0.45	T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.0	B;.;B;.;.
Vest4		0.13
MPC		0.10
ClinPred		0.0010	T
GERP RS		0.50
Varity_R		0.040
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs373533; hg19: chr19-6919624; COSMIC: COSV51673014;