Variant 6-47708258-C-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_153838.5(ADGRF4):c.128C>A(p.Pro43His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,786 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: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ADGRF4
NM_153838.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.385

Variant links:

Genes affected

ADGRF4 (HGNC:19011): (adhesion G protein-coupled receptor F4) Sequence analysis of this gene suggests that it is encodes a member of the superfamily of G protein-couple receptors. G protein-coupled receptors typically contain seven hydrophobic transmembrane domains, interact with guanine nucleotide binding regulatory proteins, and detect molecules outside the cell and act to transduce these signals into intracellular responses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

ADGRF4 links:

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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=0.037958592).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRF4	NM_153838.5 link	c.128C>A	p.Pro43His	missense_variant	3/10	ENST00000283303.3	NP_722580.3
ADGRF4	NM_001347855.2 link	c.128C>A	p.Pro43His	missense_variant	3/10		NP_001334784.1	Q8IZF3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ADGRF4	ENST00000283303.3 link	c.128C>A	p.Pro43His	missense_variant	3/10	1	NM_153838.5	ENSP00000283303.2	Q8IZF3
ADGRF4	ENST00000371220.5 link	c.299C>A	p.Pro100His	missense_variant	4/11	5		ENSP00000360264.1	A0A0C4DFV3
ADGRF4	ENST00000327753.7 link	c.128C>A	p.Pro43His	missense_variant	3/10	2		ENSP00000328319.3	Q8IZF3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459786

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726388

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The c.128C>A (p.P43H) alteration is located in exon 3 (coding exon 2) of the ADGRF4 gene. This alteration results from a C to A substitution at nucleotide position 128, causing the proline (P) at amino acid position 43 to be replaced by a histidine (H). 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

0.079

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.8

DANN

Benign

0.52

DEOGEN2

Benign

0.0059

.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.56

T;.;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.97

PrimateAI

Benign

0.22

PROVEAN

Benign

0.18

N;N;N

REVEL

Benign

0.036

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0010

.;B;B

Vest4

0.12

MutPred

0.14

.;Loss of glycosylation at P43 (P = 0.0928);Loss of glycosylation at P43 (P = 0.0928);

MVP

0.12

MPC

0.038

ClinPred

0.11

GERP RS

-0.83

Varity_R

0.049

gMVP

0.18

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