3-120348841-C-T

Position:

• chr3-120348841-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000295628.4(LRRC58):​c.403G>A​(p.Val135Met) 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 1,452,458 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LRRC58 ENST00000295628.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0320

Genes affected

LRRC58 (HGNC:26968): (leucine rich repeat containing 58)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097557396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC58	NM_001099678.2	c.403G>A	p.Val135Met	missense_variant	1/4	ENST00000295628.4	NP_001093148.1
LRRC58	XM_047447401.1	c.403G>A	p.Val135Met	missense_variant	1/3		XP_047303357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC58	ENST00000295628.4	c.403G>A	p.Val135Met	missense_variant	1/4	1	NM_001099678.2	ENSP00000295628.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452458 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721658

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: 0.0000712

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Dec 20, 2023

The c.403G>A (p.V135M) alteration is located in exon 1 (coding exon 1) of the LRRC58 gene. This alteration results from a G to A substitution at nucleotide position 403, causing the valine (V) at amino acid position 135 to be replaced by a methionine (M). 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	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.54	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.039
Sift	Benign	0.093	T
Sift4G	Benign	0.11	T
Polyphen		0.0090	B
Vest4		0.10
MutPred		0.62		Gain of disorder (P = 0.0564);
MVP		0.39
MPC		0.84
ClinPred		0.29	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.38

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: rs754019577; hg19: chr3-120067688;