Variant 19-50518194-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001080457.2(LRRC4B):c.1519C>T(p.Arg507Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000933 in 1,608,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LRRC4B
NM_001080457.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.35

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3523071).

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC4B	NM_001080457.2 linkuse as main transcript	c.1519C>T	p.Arg507Trp	missense_variant	3/3	ENST00000652263.1	NP_001073926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRRC4B	ENST00000652263.1 linkuse as main transcript	c.1519C>T	p.Arg507Trp	missense_variant	3/3		NM_001080457.2	ENSP00000498662.1	Q9NT99
LRRC4B	ENST00000389201.7 linkuse as main transcript	c.1519C>T	p.Arg507Trp	missense_variant	3/3	2		ENSP00000373853.3	Q9NT99
LRRC4B	ENST00000599957.5 linkuse as main transcript	c.1519C>T	p.Arg507Trp	missense_variant	3/3	3		ENSP00000471502.1	Q9NT99

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229816

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127492

show subpopulations

Gnomad AFR exome

AF:

0.0000748

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456216

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724490

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

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

AF:

0.0000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 28, 2024

The c.1519C>T (p.R507W) alteration is located in exon 3 (coding exon 2) of the LRRC4B gene. This alteration results from a C to T substitution at nucleotide position 1519, causing the arginine (R) at amino acid position 507 to be replaced by a tryptophan (W). 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

0.18

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

0.047

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

.;T

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.69

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.073

Sift

Uncertain

0.0030

.;D

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;D

Vest4

0.21

MVP

0.69

MPC

2.1

ClinPred

0.38

GERP RS

3.1

Varity_R

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over