rs111589388

Positions:

• chr6-142370518-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198569.3(ADGRG6):​c.794G>C​(p.Gly265Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,613,576 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (8 hom.)
• Consequence: ADGRG6 NM_198569.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.99

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005778134).
• BP6: Variant 6-142370518-G-C is Benign according to our data. Variant chr6-142370518-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 377371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00576 (877/152278) while in subpopulation AFR AF= 0.0204 (846/41560). AF 95% confidence interval is 0.0192. There are 14 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG6	NM_198569.3	c.794G>C	p.Gly265Ala	missense_variant	4/25	ENST00000367609.8	NP_940971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG6	ENST00000367609.8	c.794G>C	p.Gly265Ala	missense_variant	4/25	1	NM_198569.3	ENSP00000356581

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 874 AN: 152160 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00134 AC: 333 AN: 248942 Hom.: 5 AF XY: 0.00101 AC XY: 136 AN XY: 135046

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000828

GnomAD4 exome AF: 0.000589 AC: 861 AN: 1461298 Hom.: 8 Cov.: 32 AF XY: 0.000492 AC XY: 358 AN XY: 726998

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00142

GnomAD4 genome AF: 0.00576 AC: 877 AN: 152278 Hom.: 14 Cov.: 32 AF XY: 0.00560 AC XY: 417 AN XY: 74458

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00167 Hom.: 2

Bravo AF: 0.00646

ESP6500AA AF: 0.0193 AC: 70

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00160 AC: 193

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;D
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.026	D;D;D;D
Polyphen		0.86	P;P;P;P
Vest4		0.48
MVP		0.56
MPC		0.49
ClinPred		0.022	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.097
gMVP		0.81

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: rs111589388; hg19: chr6-142691655;