11-40115328-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001258419.2(LRRC4C):c.965C>T(p.Ser322Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: LRRC4C NM_001258419.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, LRRC4C
• BP4: Computational evidence support a benign effect (MetaRNN=0.061034232).
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC4C	NM_001258419.2	c.965C>T	p.Ser322Leu	missense_variant	7/7	ENST00000528697.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC4C	ENST00000528697.6	c.965C>T	p.Ser322Leu	missense_variant	7/7	1	NM_001258419.2	P1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 250776 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135508

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74466

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.000295

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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 17, 2023

The c.965C>T (p.S322L) alteration is located in exon 2 (coding exon 1) of the LRRC4C gene. This alteration results from a C to T substitution at nucleotide position 965, causing the serine (S) at amino acid position 322 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.061	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.95	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D;.;D;D;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.43	B;B;B;B;B
Vest4		0.30
MVP		0.18
MPC		0.71
ClinPred		0.082	T
GERP RS		5.8
Varity_R		0.44
gMVP		0.62

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: rs202082491; hg19: chr11-40136878; COSMIC: COSV53433546; COSMIC: COSV53433546;