19-6897302-C-T

Variant summary

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

The NM_001974.5(ADGRE1):​c.392C>T​(p.Thr131Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 28)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADGRE1
NM_001974.5 missense, splice_region

Scores

1
17
Splicing: ADA: 0.01398
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRE1NM_001974.5 linkc.392C>T p.Thr131Ile missense_variant, splice_region_variant 4/21 ENST00000312053.9 NP_001965.3 Q14246-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRE1ENST00000312053.9 linkc.392C>T p.Thr131Ile missense_variant, splice_region_variant 4/211 NM_001974.5 ENSP00000311545.3 Q14246-1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2024The c.392C>T (p.T131I) alteration is located in exon 4 (coding exon 4) of the ADGRE1 gene. This alteration results from a C to T substitution at nucleotide position 392, causing the threonine (T) at amino acid position 131 to be replaced by an isoleucine (I). 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
Benign
0.14
BayesDel_addAF
Benign
-0.040
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
15
DANN
Benign
0.79
DEOGEN2
Benign
0.12
.;T;.;.
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.80
T;T;D;T
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.52
D;D;D;D
MetaSVM
Benign
-0.45
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-2.3
N;N;N;.
REVEL
Benign
0.16
Sift
Benign
0.12
T;T;T;.
Sift4G
Benign
0.066
T;D;T;D
Polyphen
0.90
P;P;.;.
Vest4
0.47
MutPred
0.31
Loss of disorder (P = 0.0399);Loss of disorder (P = 0.0399);Loss of disorder (P = 0.0399);.;
MVP
0.61
MPC
0.16
ClinPred
0.16
T
GERP RS
1.5
Varity_R
0.10
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.014
dbscSNV1_RF
Benign
0.39
SpliceAI score (max)
0.17
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: chr19-6897313; API