6-142309551-C-T

Variant names:

• chr6-142309551-C-T
• rs756333358
• NM_198569.3:c.10C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_198569.3(ADGRG6):​c.10C>T​(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,606,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: ADGRG6 NM_198569.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.821

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048262626).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000022 (32/1454376) while in subpopulation MID AF= 0.000174 (1/5762). AF 95% confidence interval is 0.0000547. There are 0 homozygotes in gnomad4_exome. There are 20 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG6	NM_198569.3	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 25	ENST00000367609.8	NP_940971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG6	ENST00000367609.8	c.10C>T	p.Arg4Cys	missense_variant	Exon 2 of 25	1	NM_198569.3	ENSP00000356581.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000331 AC: 8 AN: 241550 Hom.: 0 AF XY: 0.0000383 AC XY: 5 AN XY: 130698

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000170

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 32 AN: 1454376 Hom.: 0 Cov.: 29 AF XY: 0.0000277 AC XY: 20 AN XY: 723052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151820 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74168

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000497 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10C>T (p.R4C) alteration is located in exon 2 (coding exon 2) of the ADGRG6 gene. This alteration results from a C to T substitution at nucleotide position 10, causing the arginine (R) at amino acid position 4 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	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.85	N;N;N;N;N;N
REVEL	Benign	0.092
Sift	Uncertain	0.027	D;D;D;D;D;T
Sift4G	Benign	0.19	.;.;.;.;T;T
Polyphen		0.91	P;P;P;P;P;.
Vest4		0.18
MutPred		0.39		Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);Loss of MoRF binding (P = 3e-04);.;.;
MVP		0.19
MPC		0.35
ClinPred		0.13	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.56

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: rs756333358; hg19: chr6-142630688; COSMIC: COSV51598734;