rs3741194

Positions:

• chr11-66858763-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024036.5(LRFN4):​c.1019T>C​(p.Val340Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,550,842 control chromosomes in the GnomAD database, including 49,530 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.19 (3475 hom., cov: 33)
  • Exomes 𝑓: 0.25 (46055 hom.)
• Consequence: LRFN4 NM_024036.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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]

PC (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019652247).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRFN4	NM_024036.5	c.1019T>C	p.Val340Ala	missense_variant	1/2	ENST00000309602.5	NP_076941.2
PC	NM_001040716.2	c.1368+5011A>G		intron_variant		ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRFN4	ENST00000309602.5	c.1019T>C	p.Val340Ala	missense_variant	1/2	1	NM_024036.5	ENSP00000312535.4
PC	ENST00000393960.7	c.1368+5011A>G		intron_variant		5	NM_001040716.2	ENSP00000377532.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29187 AN: 152016 Hom.: 3478 Cov.: 33

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.212 AC: 31385 AN: 148280 Hom.: 3796 AF XY: 0.215 AC XY: 17096 AN XY: 79642

Gnomad AFR exome AF: 0.0394

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.314

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.251 AC: 350705 AN: 1398708 Hom.: 46055 Cov.: 34 AF XY: 0.249 AC XY: 171814 AN XY: 690020

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.149

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.271

Gnomad4 OTH exome AF: 0.238

GnomAD4 genome AF: 0.192 AC: 29175 AN: 152134 Hom.: 3475 Cov.: 33 AF XY: 0.192 AC XY: 14268 AN XY: 74382

Gnomad4 AFR AF: 0.0491

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.270

Gnomad4 NFE AF: 0.266

Gnomad4 OTH AF: 0.223

Alfa AF: 0.257 Hom.: 4620

Bravo AF: 0.182

TwinsUK AF: 0.266 AC: 988

ALSPAC AF: 0.268 AC: 1031

ESP6500AA AF: 0.0541 AC: 231

ESP6500EA AF: 0.241 AC: 2030

ExAC AF: 0.139 AC: 14419

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.065	.;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.11
Sift	Benign	0.095	T;D
Sift4G	Uncertain	0.050	T;D
Polyphen		0.24	.;B
Vest4		0.11
MPC		1.8
ClinPred		0.044	T
GERP RS		4.0
Varity_R		0.22
gMVP		0.54

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: rs3741194; hg19: chr11-66626234; COSMIC: COSV58921962; COSMIC: COSV58921962;