NM_024509.2:c.178C>T

Variant names:

• chr19-35939603-C-T
• rs912468422
• NM_024509.2:c.178C>T

Variant summary

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

The NM_024509.2(LRFN3):​c.178C>T​(p.Arg60Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,608,840 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. R60Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LRFN3 NM_024509.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0190
• Publications: 0 publications found

Genes affected

LRFN3 (HGNC:28370): (leucine rich repeat and fibronectin type III domain containing 3) Predicted to be involved in regulation of presynapse assembly; regulation of synaptic membrane adhesion; and synaptic membrane adhesion. Predicted to be located in plasma membrane. Predicted to be active in cell surface and glutamatergic synapse. Predicted to be integral component of postsynaptic density membrane and integral component of presynaptic active zone membrane. [provided by Alliance of Genome Resources, Apr 2022]

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_024509.2. 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
	LRFN3	NM_024509.2	MANE Select	c.178C>T	p.Arg60Trp	missense	Exon 2 of 3	NP_078785.1	Q9BTN0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRFN3	ENST00000246529.4	TSL:1 MANE Select	c.178C>T	p.Arg60Trp	missense	Exon 2 of 3	ENSP00000246529.3	Q9BTN0
	LRFN3	ENST00000588831.5	TSL:5	c.178C>T	p.Arg60Trp	missense	Exon 3 of 4	ENSP00000466989.1	Q9BTN0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

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 AF: 0.00000275 AC: 4 AN: 1456610 Hom.: 0 Cov.: 33 AF XY: 0.00000414 AC XY: 3 AN XY: 724776

African (AFR) AF: 0.0000299 AC: 1 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111400

Other (OTH) AF: 0.0000166 AC: 1 AN: 60280

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.65
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.076
FATHMM_MKL	Benign	0.30	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.019
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.58		Loss of disorder (P = 0.0037)
MVP		0.43
MPC		1.9
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.46
gMVP		0.74
Mutation Taster		=75/25	polymorphism

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: rs912468422; hg19: chr19-36430505; COSMIC: COSV55817736; COSMIC: COSV55817736;