Genetic Variant ADGRL4:p.Val561Leu (chr1-78917831-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_022159.4(ADGRL4):c.1681G>T(p.Val561Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V561I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADGRL4
NM_022159.4 missense, splice_region

Scores

Splicing: ADA: 0.9854

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

Genes affected

ADGRL4 (HGNC:20822): (adhesion G protein-coupled receptor L4) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway. Predicted to be located in cytoplasmic vesicle and plasma membrane. Predicted to be integral component of plasma membrane. Biomarker of glioblastoma and hypertrophic cardiomyopathy. [provided by Alliance of Genome Resources, Apr 2022]

ADGRL4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRL4	NM_022159.4	MANE Select	c.1681G>T	p.Val561Leu	missense splice_region	Exon 11 of 15	NP_071442.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRL4	ENST00000370742.4	TSL:1 MANE Select	c.1681G>T	p.Val561Leu	missense splice_region	Exon 11 of 15	ENSP00000359778.3	Q9HBW9
ADGRL4	ENST00000954023.1		c.1711G>T	p.Val571Leu	missense splice_region	Exon 11 of 15	ENSP00000624082.1
ADGRL4	ENST00000870761.1		c.1579G>T	p.Val527Leu	missense splice_region	Exon 11 of 15	ENSP00000540820.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459894

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33362

American (AMR)

AF:

0.00

AC:

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110594

Other (OTH)

AF:

0.00

AC:

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-1.1

PhyloP100

7.9

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-2.2

REVEL

Benign

0.20

Sift

Benign

0.57

Sift4G

Uncertain

0.015

Polyphen

0.64

Vest4

0.77

MutPred

0.37

Loss of methylation at K560 (P = 0.0377)

MVP

0.70

MPC

0.28

ClinPred

0.77

GERP RS

5.8

PromoterAI

-0.0044

Neutral

(source)

Varity_R

0.53

gMVP

0.72

Mutation Taster

=18/82

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over