11-66858090-C-T

Position:

• chr11-66858090-C-T

Variant summary

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

The NM_024036.5(LRFN4):​c.346C>T​(p.Leu116Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRFN4 NM_024036.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.418

Genes affected

LRFN4 (HGNC:28456): (leucine rich repeat and fibronectin type III domain containing 4) Predicted to be involved in regulation of postsynaptic density assembly; regulation of presynapse assembly; and synaptic membrane adhesion. Predicted to be located in plasma membrane. Predicted to be active in GABA-ergic synapse; cell surface; and glutamatergic synapse. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.09896156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRFN4	NM_024036.5	c.346C>T	p.Leu116Phe	missense_variant	1/2	ENST00000309602.5
PC	NM_001040716.2	c.1369-4707G>A		intron_variant		ENST00000393960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRFN4	ENST00000309602.5	c.346C>T	p.Leu116Phe	missense_variant	1/2	1	NM_024036.5	P1
PC	ENST00000393960.7	c.1369-4707G>A		intron_variant		5	NM_001040716.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457260 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724630

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: 0.00000270

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.346C>T (p.L116F) alteration is located in exon 1 (coding exon 1) of the LRFN4 gene. This alteration results from a C to T substitution at nucleotide position 346, causing the leucine (L) at amino acid position 116 to be replaced by a phenylalanine (F). 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	0.31
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.44	.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.14
Sift	Benign	0.99	T;T
Sift4G	Benign	0.72	T;T
Polyphen		0.71	.;P
Vest4		0.20
MutPred		0.70		Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.32
MPC		2.1
ClinPred		0.41	T
GERP RS		4.2
Varity_R		0.099
gMVP		0.66

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: chr11-66625561;