19-35939670-T-C

Variant names:

• chr19-35939670-T-C
• NM_024509.2:c.245T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024509.2(LRFN3):​c.245T>C​(p.Met82Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LRFN3 NM_024509.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRFN3	NM_024509.2	c.245T>C	p.Met82Thr	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.245T>C	p.Met82Thr	missense_variant	Exon 2 of 3	1	NM_024509.2	ENSP00000246529.3
LRFN3	ENST00000588831.5	c.245T>C	p.Met82Thr	missense_variant	Exon 3 of 4	5		ENSP00000466989.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455506 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 724242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245T>C (p.M82T) alteration is located in exon 2 (coding exon 1) of the LRFN3 gene. This alteration results from a T to C substitution at nucleotide position 245, causing the methionine (M) at amino acid position 82 to be replaced by a threonine (T). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	.;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.77		Loss of stability (P = 0.0457);Loss of stability (P = 0.0457);
MVP		0.60
MPC		1.9
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.89
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36430572;