19-50518315-G-T

Position:

• chr19-50518315-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001080457.2(LRRC4B):​c.1398C>A​(p.Ser466Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LRRC4B NM_001080457.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.244

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]

LOC124904747 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.102200925).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC4B	NM_001080457.2	c.1398C>A	p.Ser466Arg	missense_variant	3/3	ENST00000652263.1	NP_001073926.1
LOC124904747	XR_007067300.1	n.54+6844G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC4B	ENST00000652263.1	c.1398C>A	p.Ser466Arg	missense_variant	3/3		NM_001080457.2	ENSP00000498662	P1
LRRC4B	ENST00000389201.7	c.1398C>A	p.Ser466Arg	missense_variant	3/3	2		ENSP00000373853	P1
LRRC4B	ENST00000599957.5	c.1398C>A	p.Ser466Arg	missense_variant	3/3	3		ENSP00000471502	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1453006 Hom.: 0 Cov.: 33 AF XY: 0.00000692 AC XY: 5 AN XY: 722630

Gnomad4 AFR exome AF: 0.00

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: 0.00000451

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.1398C>A (p.S466R) alteration is located in exon 3 (coding exon 2) of the LRRC4B gene. This alteration results from a C to A substitution at nucleotide position 1398, causing the serine (S) at amino acid position 466 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.4
DANN	Benign	0.96
DEOGEN2	Benign	0.0053	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.37	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.13	.;N
REVEL	Benign	0.012
Sift	Benign	0.073	.;T
Sift4G	Benign	0.15	T;T
Polyphen		0.13	B;B
Vest4		0.13
MutPred		0.28		Loss of glycosylation at S466 (P = 1e-04);Loss of glycosylation at S466 (P = 1e-04);
MVP		0.39
MPC		1.2
ClinPred		0.080	T
GERP RS		1.5
Varity_R		0.048

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

Other links and lift over

dbSNP: rs1017785351; hg19: chr19-51021572;