6-47005872-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_153840.4(ADGRF1):​c.2537G>A​(p.Arg846Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,288 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R846L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ADGRF1
NM_153840.4 missense

Scores

1
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.25
Variant links:
Genes affected
ADGRF1 (HGNC:18990): (adhesion G protein-coupled receptor F1) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Predicted to act upstream of or within several processes, including memory; nervous system development; and positive regulation of CREB transcription factor activity. Predicted to be located in extracellular region and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ADGRF1NM_153840.4 linkc.2537G>A p.Arg846Gln missense_variant Exon 13 of 15 ENST00000371253.7 NP_722582.2 Q5T601-1
ADGRF1XM_047418639.1 linkc.1949G>A p.Arg650Gln missense_variant Exon 7 of 9 XP_047274595.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ADGRF1ENST00000371253.7 linkc.2537G>A p.Arg846Gln missense_variant Exon 13 of 15 1 NM_153840.4 ENSP00000360299.2 Q5T601-1
ADGRF1ENST00000283297.5 linkc.1946G>A p.Arg649Gln missense_variant Exon 7 of 9 1 ENSP00000283297.5 A0A0C4DH10
ADGRF1ENST00000449332.6 linkn.2508G>A non_coding_transcript_exon_variant Exon 11 of 13 1
ADGRF1ENST00000419892.6 linkn.8803G>A non_coding_transcript_exon_variant Exon 11 of 13 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152064
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:
0.000193
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
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248710
Hom.:
0
AF XY:
0.00000744
AC XY:
1
AN XY:
134482
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000294
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.0000331
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000754
AC:
11
AN:
1458106
Hom.:
0
Cov.:
28
AF XY:
0.00000414
AC XY:
3
AN XY:
725414
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.0000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000721
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000277
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2537G>A (p.R846Q) alteration is located in exon 13 (coding exon 12) of the ADGRF1 gene. This alteration results from a G to A substitution at nucleotide position 2537, causing the arginine (R) at amino acid position 846 to be replaced by a glutamine (Q). 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
0.10
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.026
T;T
Eigen
Benign
0.13
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.011
T
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Benign
-1.1
T
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.79
N;N
REVEL
Benign
0.11
Sift
Benign
0.83
T;T
Sift4G
Benign
0.16
T;T
Polyphen
0.77
P;.
Vest4
0.62
MutPred
0.62
Loss of ubiquitination at K844 (P = 0.0587);.;
MVP
0.41
MPC
0.34
ClinPred
0.87
D
GERP RS
5.0
Varity_R
0.096
gMVP
0.57

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs764410144; hg19: chr6-46973609; API