Genetic Variant LRRC4B:p.Asn425Ser (chr19-50518439-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001080457.2(LRRC4B):c.1274A>G(p.Asn425Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,550,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

LRRC4B
NM_001080457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00

Variant links:

Genes affected

LRRC4B (HGNC:25042): (leucine rich repeat containing 4B) Predicted to enable signaling receptor binding activity. Predicted to be involved in regulation of synapse assembly and synaptic membrane adhesion. Predicted to be located in cerebellar mossy fiber and presynaptic membrane. Predicted to be active in glutamatergic synapse and plasma membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC4B links:

LOC124904747 (HGNC:):

LOC124904747 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity LRC4B_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.15770936).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC4B	NM_001080457.2 link	c.1274A>G	p.Asn425Ser	missense_variant	Exon 3 of 3	ENST00000652263.1	NP_001073926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRRC4B	ENST00000652263.1 link	c.1274A>G	p.Asn425Ser	missense_variant	Exon 3 of 3		NM_001080457.2	ENSP00000498662.1	Q9NT99
LRRC4B	ENST00000389201.7 link	c.1274A>G	p.Asn425Ser	missense_variant	Exon 3 of 3	2		ENSP00000373853.3	Q9NT99
LRRC4B	ENST00000599957.5 link	c.1274A>G	p.Asn425Ser	missense_variant	Exon 3 of 3	3		ENSP00000471502.1	Q9NT99

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000502

AC:

AN:

199050

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000500

AC:

AN:

1398912

Hom.:

Cov.:

AF XY:

0.00000871

AC XY:

AN XY:

689190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31830

American (AMR)

AF:

0.00

AC:

AN:

36298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21910

East Asian (EAS)

AF:

0.00

AC:

AN:

39152

South Asian (SAS)

AF:

0.00

AC:

AN:

76060

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48868

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00000647

AC:

AN:

1081696

Other (OTH)

AF:

0.00

AC:

AN:

57624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151986

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1274A>G (p.N425S) alteration is located in exon 3 (coding exon 2) of the LRRC4B gene. This alteration results from a A to G substitution at nucleotide position 1274, causing the asparagine (N) at amino acid position 425 to be replaced by a serine (S). 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

0.29

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.036

T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.079

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.0038

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L

PhyloP100

8.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.7

.;N

REVEL

Benign

0.075

Sift

Benign

0.29

.;T

Sift4G

Benign

0.078

T;T

Polyphen

0.0080

B;B

Vest4

0.38

MVP

0.39

MPC

0.86

ClinPred

0.37

GERP RS

3.6

Varity_R

0.10

Mutation Taster

=64/36

polymorphism

(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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chr19-50518439-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over