2-26310718-T-G

Variant names:

• chr2-26310718-T-G
• rs781185576
• NM_001321971.2:c.2806A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001321971.2(ADGRF3):​c.2806A>C​(p.Ile936Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,460,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I936V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ADGRF3 NM_001321971.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10737622).

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.2806A>C	p.Ile936Leu	missense	Exon 10 of 14	NP_001308900.1	A0A494C083
	ADGRF3	NM_001145168.1		c.3010A>C	p.Ile1004Leu	missense	Exon 11 of 13	NP_001138640.1	Q8IZF5-1
	ADGRF3	NM_001145169.1		c.2803A>C	p.Ile935Leu	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.2806A>C	p.Ile936Leu	missense	Exon 10 of 14	ENSP00000498434.1	A0A494C083
	ADGRF3	ENST00000311519.5	TSL:1	c.3010A>C	p.Ile1004Leu	missense	Exon 11 of 13	ENSP00000307831.1	Q8IZF5-1
	ADGRF3	ENST00000447444.5	TSL:1	n.2413A>C		non_coding_transcript_exon	Exon 8 of 13	ENSP00000404775.1	Q8IZF5-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 245960 AF XY: 0.0000150

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: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1460256 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726278

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111284

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.26
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.46
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.33	T
Sift4G	Benign	0.80	T
Polyphen		0.0010	B
Vest4		0.18
MutPred		0.34		Gain of catalytic residue at I1004 (P = 0.2026)
MVP		0.11
MPC		0.084
ClinPred		0.027	T
GERP RS		-3.5
Varity_R		0.10
gMVP		0.077
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781185576; hg19: chr2-26533586;