19-35940299-G-A

Position:

• chr19-35940299-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000246529.4(LRFN3):​c.874G>A​(p.Val292Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRFN3 ENST00000246529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14320579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRFN3	NM_024509.2	c.874G>A	p.Val292Ile	missense_variant	2/3	ENST00000246529.4	NP_078785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRFN3	ENST00000246529.4	c.874G>A	p.Val292Ile	missense_variant	2/3	1	NM_024509.2	ENSP00000246529.3
LRFN3	ENST00000588831.5	c.874G>A	p.Val292Ile	missense_variant	3/4	5		ENSP00000466989.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

The c.874G>A (p.V292I) 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 874, causing the valine (V) at amino acid position 292 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0076	T;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.10	.;N
REVEL	Benign	0.064
Sift	Benign	0.33	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.020	B;B
Vest4		0.11
MutPred		0.34		Loss of disorder (P = 0.0762);Loss of disorder (P = 0.0762);
MVP		0.12
MPC		0.66
ClinPred		0.38	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.24

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: chr19-36431201;