6-47712599-G-C

Position:

• chr6-47712599-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153838.5(ADGRF4):​c.543G>C​(p.Glu181Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,570,638 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 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ADGRF4 NM_153838.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08256602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRF4	NM_153838.5	c.543G>C	p.Glu181Asp	missense_variant	5/10	ENST00000283303.3	NP_722580.3
ADGRF4	NM_001347855.2	c.543G>C	p.Glu181Asp	missense_variant	5/10		NP_001334784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRF4	ENST00000283303.3	c.543G>C	p.Glu181Asp	missense_variant	5/10	1	NM_153838.5	ENSP00000283303.2
ADGRF4	ENST00000371220.5	c.714G>C	p.Glu238Asp	missense_variant	6/11	5		ENSP00000360264.1
ADGRF4	ENST00000327753.7	c.543G>C	p.Glu181Asp	missense_variant	5/10	2		ENSP00000328319.3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000397

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000234 AC: 58 AN: 248188 Hom.: 0 AF XY: 0.000282 AC XY: 38 AN XY: 134618

Gnomad AFR exome AF: 0.0000642

Gnomad AMR exome AF: 0.000379

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: 0.000392

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 354 AN: 1418452 Hom.: 0 Cov.: 27 AF XY: 0.000267 AC XY: 189 AN XY: 707884

Gnomad4 AFR exome AF: 0.0000923

Gnomad4 AMR exome AF: 0.000270

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.000153

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74350

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000436

EpiControl AF: 0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.543G>C (p.E181D) alteration is located in exon 5 (coding exon 4) of the ADGRF4 gene. This alteration results from a G to C substitution at nucleotide position 543, causing the glutamic acid (E) at amino acid position 181 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.0040	.;T;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.38	T;.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.63	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.0040	.;B;B
Vest4		0.094
MutPred		0.28		.;Loss of ubiquitination at K182 (P = 0.0642);Loss of ubiquitination at K182 (P = 0.0642);
MVP		0.25
MPC		0.036
ClinPred		0.057	T
GERP RS		1.1
Varity_R		0.045
gMVP		0.24

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: rs140892790; hg19: chr6-47680335;