chr11-66858763-T-C

Variant names:

• chr11-66858763-T-C
• rs3741194
• NM_024036.5:c.1019T>C

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• pyruvate carboxylase deficiency disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• pyruvate carboxylase deficiency, benign type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• pyruvate carboxylase deficiency, severe neonatal type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024036.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRFN4	NM_024036.5	MANE Select	c.1019T>C	p.Val340Ala	missense	Exon 1 of 2	NP_076941.2
	PC	NM_001040716.2	MANE Select	c.1368+5011A>G		intron	N/A	NP_001035806.1	P11498-1
	LRFN4	NM_001363524.2		c.1019T>C	p.Val340Ala	missense	Exon 2 of 3	NP_001350453.1	Q6PJG9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRFN4	ENST00000309602.5	TSL:1 MANE Select	c.1019T>C	p.Val340Ala	missense	Exon 1 of 2	ENSP00000312535.4	Q6PJG9
	PC	ENST00000393960.7	TSL:5 MANE Select	c.1368+5011A>G		intron	N/A	ENSP00000377532.1	P11498-1
	PC	ENST00000393955.6	TSL:1	c.1368+5011A>G		intron	N/A	ENSP00000377527.2	P11498-1

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

GnomAD2 exomes AF: 0.212 AC: 31385 AN: 148280 AF XY: 0.215

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 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

African (AFR) AF: 0.0402 AC: 1278 AN: 31794

American (AMR) AF: 0.148 AC: 5325 AN: 35870

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7676 AN: 25142

East Asian (EAS) AF: 0.149 AC: 5385 AN: 36050

South Asian (SAS) AF: 0.134 AC: 10684 AN: 79564

European-Finnish (FIN) AF: 0.274 AC: 12877 AN: 47050

Middle Eastern (MID) AF: 0.272 AC: 1548 AN: 5684

European-Non Finnish (NFE) AF: 0.271 AC: 292157 AN: 1079586

Other (OTH) AF: 0.238 AC: 13775 AN: 57968

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

African (AFR) AF: 0.0491 AC: 2039 AN: 41534

American (AMR) AF: 0.187 AC: 2865 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3472

East Asian (EAS) AF: 0.155 AC: 798 AN: 5162

South Asian (SAS) AF: 0.141 AC: 681 AN: 4820

European-Finnish (FIN) AF: 0.270 AC: 2860 AN: 10594

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18104 AN: 67946

Other (OTH) AF: 0.223 AC: 470 AN: 2110

Alfa AF: 0.254 Hom.: 5381

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 v4.9

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
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.065	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.11
Sift	Benign	0.095	T
Sift4G	Uncertain	0.050	T
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
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

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