1-78920373-T-C

Position:

• chr1-78920373-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_022159.4(ADGRL4):​c.1271A>G​(p.Tyr424Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRL4 NM_022159.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.16

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL4	NM_022159.4	c.1271A>G	p.Tyr424Cys	missense_variant	10/15	ENST00000370742.4	NP_071442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL4	ENST00000370742.4	c.1271A>G	p.Tyr424Cys	missense_variant	10/15	1	NM_022159.4	ENSP00000359778	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

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

Oct 06, 2022

The c.1271A>G (p.Y424C) alteration is located in exon 10 (coding exon 10) of the ADGRL4 gene. This alteration results from a A to G substitution at nucleotide position 1271, causing the tyrosine (Y) at amino acid position 424 to be replaced by a cysteine (C). 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	0.26
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.24
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.96	D
Vest4		0.83
MutPred		0.57		Loss of ubiquitination at K422 (P = 0.0962);
MVP		0.57
MPC		0.26
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.10
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-79386058;