dbSNP rs1968956: ADGRL4:p.His599Gln (chr1-78893142-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_022159.4(ADGRL4):c.1797C>A(p.His599Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,602,552 control chromosomes in the GnomAD database, including 1,031 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.023 ( 59 hom., cov: 32)

Exomes 𝑓: 0.034 ( 972 hom. )

Consequence

ADGRL4
NM_022159.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.253

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008930951).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0234 (3530/151004) while in subpopulation NFE AF= 0.0377 (2551/67742). AF 95% confidence interval is 0.0364. There are 59 homozygotes in gnomad4. There are 1598 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRL4	NM_022159.4 link	c.1797C>A	p.His599Gln	missense_variant	Exon 13 of 15	ENST00000370742.4	NP_071442.2	Q9HBW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRL4	ENST00000370742.4 link	c.1797C>A	p.His599Gln	missense_variant	Exon 13 of 15	1	NM_022159.4	ENSP00000359778.3		Q9HBW9

Frequencies

GnomAD3 genomes

AF:

0.0234

AC:

3531

AN:

150964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00768

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.0221

Gnomad FIN

AF:

0.0168

Gnomad MID

AF:

0.00974

Gnomad NFE

AF:

0.0377

Gnomad OTH

AF:

0.0309

GnomAD3 exomes

AF:

0.0240

AC:

5790

AN:

241474

Hom.:

AF XY:

0.0251

AC XY:

3295

AN XY:

131244

show subpopulations

Gnomad AFR exome

AF:

0.00602

Gnomad AMR exome

AF:

0.0101

Gnomad ASJ exome

AF:

0.0226

Gnomad EAS exome

AF:

0.000115

Gnomad SAS exome

AF:

0.0245

Gnomad FIN exome

AF:

0.0149

Gnomad NFE exome

AF:

0.0360

Gnomad OTH exome

AF:

0.0236

GnomAD4 exome

AF:

0.0341

AC:

49545

AN:

1451548

Hom.:

972

Cov.:

AF XY:

0.0341

AC XY:

24586

AN XY:

721932

show subpopulations

Gnomad4 AFR exome

AF:

0.00472

Gnomad4 AMR exome

AF:

0.0111

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.0000765

Gnomad4 SAS exome

AF:

0.0273

Gnomad4 FIN exome

AF:

0.0178

Gnomad4 NFE exome

AF:

0.0391

Gnomad4 OTH exome

AF:

0.0292

GnomAD4 genome

AF:

0.0234

AC:

3530

AN:

151004

Hom.:

Cov.:

AF XY:

0.0217

AC XY:

1598

AN XY:

73656

show subpopulations

Gnomad4 AFR

AF:

0.00767

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.000388

Gnomad4 SAS

AF:

0.0222

Gnomad4 FIN

AF:

0.0168

Gnomad4 NFE

AF:

0.0377

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0350

Hom.:

234

Bravo

AF:

0.0224

TwinsUK

AF:

0.0343

AC:

127

ALSPAC

AF:

0.0374

AC:

144

ESP6500AA

AF:

0.00851

AC:

ESP6500EA

AF:

0.0378

AC:

308

ExAC

AF:

0.0253

AC:

3049

Asia WGS

AF:

0.0120

AC:

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

0.011

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;T

MetaRNN

Benign

0.0089

T;T

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Benign

0.16

Sift

Benign

0.062

T;D

Sift4G

Benign

0.17

T;T

Polyphen

0.20

.;B

Vest4

0.16

MutPred

0.37

.;Gain of ubiquitination at K604 (P = 0.0716);

MPC

0.20

ClinPred

0.068

GERP RS

3.6

Varity_R

0.72

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over