19-6887613-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001974.5(ADGRE1):c.5G>T(p.Arg2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,612,716 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: ADGRE1 NM_001974.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035316944).
• BP6: Variant 19-6887613-G-T is Benign according to our data. Variant chr19-6887613-G-T is described in ClinVar as [Benign]. Clinvar id is 775402.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE1	NM_001974.5	c.5G>T	p.Arg2Leu	missense_variant	1/21	ENST00000312053.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE1	ENST00000312053.9	c.5G>T	p.Arg2Leu	missense_variant	1/21	1	NM_001974.5	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2225 AN: 152126 Hom.: 64 Cov.: 31

Gnomad AFR AF: 0.0501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00408 AC: 1018 AN: 249464 Hom.: 17 AF XY: 0.00326 AC XY: 440 AN XY: 134970

Gnomad AFR exome AF: 0.0512

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00439

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000318

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00169 AC: 2467 AN: 1460472 Hom.: 46 Cov.: 30 AF XY: 0.00151 AC XY: 1098 AN XY: 726578

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.00272

Gnomad4 ASJ exome AF: 0.00452

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000139

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.0146 AC: 2227 AN: 152244 Hom.: 64 Cov.: 31 AF XY: 0.0143 AC XY: 1061 AN XY: 74426

Gnomad4 AFR AF: 0.0500

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00139 Hom.: 1

Bravo AF: 0.0171

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0520 AC: 229

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00501 AC: 608

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.000546

EpiControl AF: 0.000416

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	13
Dann	Benign	0.84
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.75	T;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.051
Sift	Benign	0.18	T;T;T;D;T
Sift4G	Benign	0.25	T;T;T;D;T
Polyphen		0.37	B;.;B;.;.
Vest4		0.41
MVP		0.39
MPC		0.13
ClinPred		0.0049	T
GERP RS		2.3
Varity_R		0.11
gMVP		0.48

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: rs34176643; hg19: chr19-6887624;