6-142408187-T-A

Position:

• chr6-142408187-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The ENST00000367609.8(ADGRG6):​c.2306T>A​(p.Val769Glu) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRG6 ENST00000367609.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.49

Genes affected

ADGRG6 (HGNC:13841): (adhesion G protein-coupled receptor G6) This gene, which is upregulated in human umbilical vein endothelial cells, encodes a G protein-coupled receptor. Variations in this gene can affect a person's stature. Multiple transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 6-142408187-T-A is Pathogenic according to our data. Variant chr6-142408187-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 192349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-142408187-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG6	NM_198569.3	c.2306T>A	p.Val769Glu	missense_variant	16/25	ENST00000367609.8	NP_940971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG6	ENST00000367609.8	c.2306T>A	p.Val769Glu	missense_variant	16/25	1	NM_198569.3	ENSP00000356581

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lethal congenital contracture syndrome 9 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 04, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with lethal congenital contracture syndrome 9 (MIM#616503). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to glutamic acid. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GAIN domain (PMID: 26004201). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. This family has been reported in PMID: 26004201. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies using transfected HEK cells showed this variant greatly reduced autoproteolytic cleavage of GPR126 protein (PMID: 26004201). In addition, evaluation of the proband’s psoas muscle revealed an almost complete absence of myelin basic protein (PMID: 26004201). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (segregation analysis by external laboratory). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Arthrogryposis multiplex congenita Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Harry Perkins Institute Of Medical Research, University Of Western Australia

Dec 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;D;D;D
Vest4		0.97
MutPred		0.72		Loss of sheet (P = 0.0817);.;.;Loss of sheet (P = 0.0817);
MVP		0.81
MPC		0.66
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.94

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

Other links and lift over

dbSNP: rs793888525; hg19: chr6-142729324;