11-40115527-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001258419.2(LRRC4C):c.766C>A(p.Gln256Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,884 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRRC4C NM_001258419.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

LRRC4C (HGNC:29317): (leucine rich repeat containing 4C) NGL1 is a specific binding partner for netrin G1 (NTNG1; MIM 608818), which is a member of the netrin family of axon guidance molecules (Lin et al., 2003 [PubMed 14595443]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, LRRC4C
• BP4: Computational evidence support a benign effect (MetaRNN=0.40983745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC4C	NM_001258419.2	c.766C>A	p.Gln256Lys	missense_variant	7/7	ENST00000528697.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC4C	ENST00000528697.6	c.766C>A	p.Gln256Lys	missense_variant	7/7	1	NM_001258419.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250980 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

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: 0.00000205 AC: 3 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00

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

Jan 04, 2022

The c.766C>A (p.Q256K) alteration is located in exon 2 (coding exon 1) of the LRRC4C gene. This alteration results from a C to A substitution at nucleotide position 766, causing the glutamine (Q) at amino acid position 256 to be replaced by a lysine (K). 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	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.040	T;T;T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.060	N;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.19	T;.;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.018	B;B;B;B;B
Vest4		0.64
MutPred		0.49		Gain of methylation at Q256 (P = 0.017);Gain of methylation at Q256 (P = 0.017);Gain of methylation at Q256 (P = 0.017);Gain of methylation at Q256 (P = 0.017);Gain of methylation at Q256 (P = 0.017);
MVP		0.52
MPC		0.91
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.53
gMVP		0.51

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: rs1314592573; hg19: chr11-40137077;