NM_198569.3:c.215G>A

Variant names:

• chr6-142367680-G-A
• rs192254609
• NM_198569.3:c.215G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_198569.3(ADGRG6):​c.215G>A​(p.Arg72Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000083 in 1,613,656 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ADGRG6 NM_198569.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.17
• Publications: 1 publications found

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]

ADGRG6 Gene-Disease associations (from GenCC):

• lethal congenital contracture syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020842314).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00046 (70/152042) while in subpopulation AMR AF = 0.00439 (67/15274). AF 95% confidence interval is 0.00354. There are 1 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198569.3. 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
	ADGRG6	NM_198569.3	MANE Select	c.215G>A	p.Arg72Gln	missense	Exon 3 of 25	NP_940971.2	Q86SQ4-3
	ADGRG6	NM_001032395.3		c.215G>A	p.Arg72Gln	missense	Exon 3 of 24	NP_001027567.2	Q86SQ4-4
	ADGRG6	NM_020455.6		c.215G>A	p.Arg72Gln	missense	Exon 3 of 26	NP_065188.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG6	ENST00000367609.8	TSL:1 MANE Select	c.215G>A	p.Arg72Gln	missense	Exon 3 of 25	ENSP00000356581.3	Q86SQ4-3
	ADGRG6	ENST00000367608.6	TSL:1	c.215G>A	p.Arg72Gln	missense	Exon 3 of 24	ENSP00000356580.2	Q86SQ4-4
	ADGRG6	ENST00000230173.10	TSL:1	c.215G>A	p.Arg72Gln	missense	Exon 3 of 26	ENSP00000230173.6	Q86SQ4-1

Frequencies

GnomAD3 genomes AF: 0.000461 AC: 70 AN: 151924 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 249106 AF XY: 0.0000962

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461614 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727090

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00101 AC: 45 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111810

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152042 Hom.: 1 Cov.: 32 AF XY: 0.000727 AC XY: 54 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00439 AC: 67 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000329

ExAC AF: 0.0000662 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.96	T
PhyloP100		4.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.077
Sift	Benign	0.27	T
Sift4G	Benign	0.064	T
Polyphen		0.88	P
Vest4		0.14
MVP		0.19
MPC		0.22
ClinPred		0.046	T
GERP RS		5.2
Varity_R		0.066
gMVP		0.51
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs192254609; hg19: chr6-142688817;