7-128029154-T-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022143.5(LRRC4):c.1487A>G(p.Gln496Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000793 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

LRRC4
NM_022143.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.13

Variant links:

Genes affected

LRRC4 (HGNC:15586): (leucine rich repeat containing 4) Predicted to be involved in modulation of chemical synaptic transmission and synapse organization. Predicted to act upstream of or within synapse organization. Predicted to be located in neuron spine and postsynaptic membrane. Predicted to be active in Schaffer collateral - CA1 synapse; glutamatergic synapse; and plasma membrane. Predicted to be integral component of postsynaptic density membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC4 links:

SND1 (HGNC:30646): (staphylococcal nuclease and tudor domain containing 1) This gene encodes a transcriptional co-activator that interacts with the acidic domain of Epstein-Barr virus nuclear antigen 2 (EBNA 2), a transcriptional activator that is required for B-lymphocyte transformation. Other transcription factors that interact with this protein are signal transducers and activators of transcription, STATs. This protein is also thought to be essential for normal cell growth. A similar protein in mammals and other organisms is a component of the RNA-induced silencing complex (RISC). [provided by RefSeq, Jul 2016]

SND1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15141574).

BS2

High AC in GnomAdExome4 at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRRC4	NM_022143.5 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 2 of 2	ENST00000249363.4	NP_071426.1	Q9HBW1
SND1	NM_014390.4 link	c.1779+38098T>C		intron_variant	Intron 16 of 23	ENST00000354725.8	NP_055205.2	Q7KZF4A0A140VK49
LRRC4	XM_011516461.4 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 3 of 3		XP_011514763.1	Q9HBW1
LRRC4	XM_047420695.1 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 3 of 3		XP_047276651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRRC4	ENST00000249363.4 link	c.1487A>G	p.Gln496Arg	missense_variant	Exon 2 of 2	1	NM_022143.5	ENSP00000249363.3		Q9HBW1
SND1	ENST00000354725.8 link	c.1779+38098T>C		intron_variant	Intron 16 of 23	1	NM_014390.4	ENSP00000346762.3		Q7KZF4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152092

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251448

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000855

AC:

125

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1487A>G (p.Q496R) alteration is located in exon 2 (coding exon 1) of the LRRC4 gene. This alteration results from a A to G substitution at nucleotide position 1487, causing the glutamine (Q) at amino acid position 496 to be replaced by an arginine (R). 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

0.074

BayesDel_addAF

Benign

-0.068

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.12

Eigen

Benign

-0.0095

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.59

M_CAP

Benign

0.013

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-0.34

REVEL

Benign

0.17

Sift

Benign

0.98

Sift4G

Benign

0.75

Polyphen

0.71

Vest4

0.25

MVP

0.66

MPC

0.52

ClinPred

0.13

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.12

gMVP

0.73

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