6-142309575-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_198569.3(ADGRG6):​c.34C>T​(p.His12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,609,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ADGRG6
NM_198569.3 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1558455).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000281 (41/1457704) while in subpopulation NFE AF= 0.0000342 (38/1109816). AF 95% confidence interval is 0.0000254. There are 0 homozygotes in gnomad4_exome. There are 12 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
ADGRG6NM_198569.3 linkc.34C>T p.His12Tyr missense_variant Exon 2 of 25 ENST00000367609.8 NP_940971.2 Q86SQ4-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADGRG6ENST00000367609.8 linkc.34C>T p.His12Tyr missense_variant Exon 2 of 25 1 NM_198569.3 ENSP00000356581.3 Q86SQ4-3

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151854
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000409
AC:
1
AN:
244208
Hom.:
0
AF XY:
0.00000756
AC XY:
1
AN XY:
132204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000905
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000281
AC:
41
AN:
1457704
Hom.:
0
Cov.:
29
AF XY:
0.0000166
AC XY:
12
AN XY:
724720
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000342
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151854
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74190
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Oct 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.34C>T (p.H12Y) 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 34, causing the histidine (H) at amino acid position 12 to be replaced by a tyrosine (Y). 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
0.076
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
19
DANN
Benign
0.93
DEOGEN2
Benign
0.12
T;.;.;.;T;.
Eigen
Benign
0.020
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D
M_CAP
Benign
0.0045
T
MetaRNN
Benign
0.16
T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.76
N;N;N;N;N;N
REVEL
Benign
0.10
Sift
Uncertain
0.0020
D;D;D;D;D;D
Sift4G
Benign
0.38
.;.;.;.;T;T
Polyphen
0.38
B;B;P;B;P;.
Vest4
0.51
MVP
0.14
MPC
0.14
ClinPred
0.20
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.16
gMVP
0.46

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1217873370; hg19: chr6-142630712; API