chr11-66858763-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.06

Publications

35 publications found

Variant links:

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]

LRFN4 links:

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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P
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

PC links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRFN4	NM_024036.5 link	c.1019T>C	p.Val340Ala	missense_variant	Exon 1 of 2	ENST00000309602.5	NP_076941.2	Q6PJG9A0A024R5I6
PC	NM_001040716.2 link	c.1368+5011A>G		intron_variant	Intron 12 of 22	ENST00000393960.7	NP_001035806.1	P11498-1A0A024R5C5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRFN4	ENST00000309602.5 link	c.1019T>C	p.Val340Ala	missense_variant	Exon 1 of 2	1	NM_024036.5	ENSP00000312535.4		Q6PJG9
PC	ENST00000393960.7 link	c.1368+5011A>G		intron_variant	Intron 12 of 22	5	NM_001040716.2	ENSP00000377532.1		P11498-1

Frequencies

GnomAD3 genomes

AF:

0.192

AC:

29187

AN:

152016

Hom.:

3478

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.249

AC XY:

171814

AN XY:

690020

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

16790

33580

50370

67160

83950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9728

19456

29184

38912

48640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.192

AC:

29175

AN:

152134

Hom.:

3475

Cov.:

AF XY:

0.192

AC XY:

14268

AN XY:

74382

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18104

AN:

67946

Other (OTH)

AF:

0.223

AC:

470

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1227

2453

3680

4906

6133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.065

.;N

PhyloP100

2.1

PrimateAI

Pathogenic

0.79

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

GERP RS

4.0

Varity_R

0.22

gMVP

0.54

Mutation Taster

=75/25

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over