Genetic Variant ADGRF5:p.Thr30Ala (chr6-46906675-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001098518.2(ADGRF5):c.88A>G(p.Thr30Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,166 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADGRF5
NM_001098518.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.425

Variant links:

Genes affected

ADGRF5 (HGNC:19030): (adhesion G protein-coupled receptor F5) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway and cell surface receptor signaling pathway. Predicted to act upstream of or within several processes, including glomerular filtration; pharyngeal arch artery morphogenesis; and surfactant homeostasis. Located in cell surface and cytoplasmic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ADGRF5 links:

ADGRF5-AS1 (HGNC:40864): (ADGRF5 antisense RNA 1)

ADGRF5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052853793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRF5	NM_001098518.2 link	c.88A>G	p.Thr30Ala	missense_variant	Exon 2 of 21	ENST00000283296.12	NP_001091988.1	Q8IZF2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRF5	ENST00000283296.12 link	c.88A>G	p.Thr30Ala	missense_variant	Exon 2 of 21	1	NM_001098518.2	ENSP00000283296.7	Q8IZF2-1
ADGRF5	ENST00000265417.7 link	c.88A>G	p.Thr30Ala	missense_variant	Exon 2 of 21	1		ENSP00000265417.6	Q8IZF2-1
ADGRF5-AS1	ENST00000451135.1 link	n.300-1193T>C		intron_variant	Intron 2 of 3	1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.20e-7

AC:

AN:

1389448

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

695950

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:

9.56e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74320

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.88A>G (p.T30A) alteration is located in exon 2 (coding exon 1) of the ADGRF5 gene. This alteration results from a A to G substitution at nucleotide position 88, causing the threonine (T) at amino acid position 30 to be replaced by an alanine (A). 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

0.061

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.061

DANN

Benign

0.43

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.29

T;.

M_CAP

Benign

0.0035

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.0090

Sift

Benign

0.28

T;T

Sift4G

Benign

0.066

T;T

Polyphen

0.0

B;B

Vest4

0.18

MutPred

0.19

Loss of glycosylation at T30 (P = 0.0097);Loss of glycosylation at T30 (P = 0.0097);

MVP

0.043

MPC

0.21

ClinPred

0.041

GERP RS

-1.4

Varity_R

0.025

gMVP

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over