chr19-14151055-C-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBS1_SupportingBS2
The NM_014921.5(ADGRL1):c.4228G>A(p.Ala1410Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00067 ( 0 hom., cov: 0)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
ADGRL1
NM_014921.5 missense
NM_014921.5 missense
Scores
1
3
14
Clinical Significance
Conservation
PhyloP100: 1.80
Genes affected
ADGRL1 (HGNC:20973): (adhesion G protein-coupled receptor L1) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane. Latrophilin-1 has been shown to recruit the neurotoxin from black widow spider venom, alpha-latrotoxin, to the synapse plasma membrane. Alternative splicing results in multiple variants encoding distinct isoforms.[provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, ADGRL1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.08075279).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000671 (8/11916) while in subpopulation AFR AF= 0.0017 (5/2946). AF 95% confidence interval is 0.000669. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRL1 | NM_014921.5 | c.4228G>A | p.Ala1410Thr | missense_variant | 23/23 | ENST00000361434.8 | |
ADGRL1-AS1 | NR_045214.1 | n.73-4097C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRL1 | ENST00000361434.8 | c.4228G>A | p.Ala1410Thr | missense_variant | 23/23 | 1 | NM_014921.5 | A1 | |
ADGRL1-AS1 | ENST00000588387.2 | n.79-4097C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000589 AC: 7AN: 11882Hom.: 0 Cov.: 0
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GnomAD3 exomes AF: 0.0000931 AC: 2AN: 21492Hom.: 0 AF XY: 0.000173 AC XY: 2AN XY: 11580
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GnomAD4 exome AF: 0.0000340 AC: 8AN: 235254Hom.: 0 Cov.: 14 AF XY: 0.0000623 AC XY: 7AN XY: 112436
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GnomAD4 genome ? AF: 0.000671 AC: 8AN: 11916Hom.: 0 Cov.: 0 AF XY: 0.000161 AC XY: 1AN XY: 6202
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2022 | The c.4243G>A (p.A1415T) alteration is located in exon 24 (coding exon 23) of the ADGRL1 gene. This alteration results from a G to A substitution at nucleotide position 4243, causing the alanine (A) at amino acid position 1415 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;P
Vest4
MutPred
Gain of phosphorylation at A1415 (P = 3e-04);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at