19-35939604-G-A

Variant names:

• chr19-35939604-G-A
• rs757480500
• NM_024509.2:c.179G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_024509.2(LRFN3):​c.179G>A​(p.Arg60Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000172 in 1,456,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R60W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: LRFN3 NM_024509.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28439522).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRFN3	NM_024509.2	c.179G>A	p.Arg60Gln	missense_variant	Exon 2 of 3	ENST00000246529.4	NP_078785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRFN3	ENST00000246529.4	c.179G>A	p.Arg60Gln	missense_variant	Exon 2 of 3	1	NM_024509.2	ENSP00000246529.3
LRFN3	ENST00000588831.5	c.179G>A	p.Arg60Gln	missense_variant	Exon 3 of 4	5		ENSP00000466989.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000212 AC: 5 AN: 235564 Hom.: 0 AF XY: 0.0000308 AC XY: 4 AN XY: 129730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000566

Gnomad SAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1456556 Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15 AN XY: 724746

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179G>A (p.R60Q) alteration is located in exon 2 (coding exon 1) of the LRFN3 gene. This alteration results from a G to A substitution at nucleotide position 179, causing the arginine (R) at amino acid position 60 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	.;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.99	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	.;N
REVEL	Benign	0.13
Sift	Benign	0.052	.;T
Sift4G	Benign	0.087	T;T
Polyphen		0.90	P;P
Vest4		0.19
MutPred		0.53		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.45
MPC		1.3
ClinPred		0.26	T
GERP RS		4.6
Varity_R		0.23
gMVP		0.55

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: rs757480500; hg19: chr19-36430506; COSMIC: COSV55818717; COSMIC: COSV55818717;