NM_001321971.2:c.2367C>G

Variant names:

• chr2-26311157-G-C
• rs1200880575
• NM_001321971.2:c.2367C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001321971.2(ADGRF3):​c.2367C>G​(p.Phe789Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. F789V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADGRF3 NM_001321971.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20
• Publications: 0 publications found

Genes affected

ADGRF3 (HGNC:18989): (adhesion G protein-coupled receptor F3) 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 be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SELENOI (HGNC:29361): (selenoprotein I) The multi-pass transmembrane protein encoded by this gene belongs to the CDP-alcohol phosphatidyltransferase class-I family. It catalyzes the transfer of phosphoethanolamine from CDP-ethanolamine to diacylglycerol to produce phosphatidylethanolamine, which is involved in the formation and maintenance of vesicular membranes, regulation of lipid metabolism, and protein folding. This protein is a selenoprotein, containing the rare selenocysteine (Sec) amino acid at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]

SELENOI Gene-Disease associations (from GenCC):

• spastic paraplegia 81, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: G2P
• neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

LOC105374334 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321971.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRF3	NM_001321971.2	MANE Select	c.2367C>G	p.Phe789Leu	missense	Exon 10 of 14	NP_001308900.1	A0A494C083
	ADGRF3	NM_001145168.1		c.2571C>G	p.Phe857Leu	missense	Exon 11 of 13	NP_001138640.1	Q8IZF5-1
	ADGRF3	NM_001145169.1		c.2364C>G	p.Phe788Leu	missense	Exon 10 of 13	NP_001138641.1	Q8IZF5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRF3	ENST00000651242.2	MANE Select	c.2367C>G	p.Phe789Leu	missense	Exon 10 of 14	ENSP00000498434.1	A0A494C083
	ADGRF3	ENST00000311519.5	TSL:1	c.2571C>G	p.Phe857Leu	missense	Exon 11 of 13	ENSP00000307831.1	Q8IZF5-1
	ADGRF3	ENST00000447444.5	TSL:1	n.1974C>G		non_coding_transcript_exon	Exon 8 of 13	ENSP00000404775.1	Q8IZF5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 217148 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444358 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 716962

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 41268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 38784

South Asian (SAS) AF: 0.00 AC: 0 AN: 83922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104042

Other (OTH) AF: 0.00 AC: 0 AN: 59808

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.72	T
PhyloP100		4.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.64		Loss of catalytic residue at F857 (P = 0.1139)
MVP		0.56
MPC		0.49
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.30
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs1200880575; hg19: chr2-26534025;