19-6897294-C-A

Variant summary

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

The NM_001974.5(ADGRE1):c.384C>A(p.Phe128Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: ADGRE1 NM_001974.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.858

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 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=0.16989389).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRE1	NM_001974.5	c.384C>A	p.Phe128Leu	missense_variant	4/21	ENST00000312053.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRE1	ENST00000312053.9	c.384C>A	p.Phe128Leu	missense_variant	4/21	1	NM_001974.5	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.384C>A (p.F128L) alteration is located in exon 4 (coding exon 4) of the ADGRE1 gene. This alteration results from a C to A substitution at nucleotide position 384, causing the phenylalanine (F) at amino acid position 128 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.0014	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	4.7
Dann	Uncertain	0.99
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.63	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;D;D;.
REVEL	Uncertain	0.38
Sift	Benign	0.088	T;T;T;.
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.27	B;P;.;.
Vest4		0.37
MutPred		0.44		Loss of methylation at K124 (P = 0.0826);Loss of methylation at K124 (P = 0.0826);Loss of methylation at K124 (P = 0.0826);.;
MVP		0.41
MPC		0.13
ClinPred		0.32	T
GERP RS		-1.1
Varity_R		0.080
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-6897305;