19-6919742-A-T

Position:

• chr19-6919742-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001974.5(ADGRE1):​c.1615A>T​(p.Ile539Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I539V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.121869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRE1	NM_001974.5	c.1615A>T	p.Ile539Phe	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>T	p.Ile539Phe	missense_variant	13/21	1	NM_001974.5	ENSP00000311545.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;.;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.63	T
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Benign	0.095
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		0.27	B;.;B;.;.
Vest4		0.26
MutPred		0.39		Loss of catalytic residue at P541 (P = 0.0423);.;Loss of catalytic residue at P541 (P = 0.0423);.;.;
MVP		0.33
MPC		0.53
ClinPred		0.87	D
GERP RS		-0.14
Varity_R		0.24
gMVP		0.11

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: rs461645; hg19: chr19-6919753;