chr11-40115420-A-T

Position:

• chr11-40115420-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001258419.2(LRRC4C):​c.873T>A​(p.His291Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: LRRC4C NM_001258419.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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 1 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=0.1361705).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRRC4C	NM_001258419.2	c.873T>A	p.His291Gln	missense_variant	7/7	ENST00000528697.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRRC4C	ENST00000528697.6	c.873T>A	p.His291Gln	missense_variant	7/7	1	NM_001258419.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

LRRC4C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2023

The LRRC4C c.873T>A variant is predicted to result in the amino acid substitution p.His291Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.064	T;T;T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;.;N;N;N
REVEL	Benign	0.074
Sift	Benign	0.38	T;.;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.023	B;B;B;B;B
Vest4		0.39
MutPred		0.31		Loss of catalytic residue at L293 (P = 0.0994);Loss of catalytic residue at L293 (P = 0.0994);Loss of catalytic residue at L293 (P = 0.0994);Loss of catalytic residue at L293 (P = 0.0994);Loss of catalytic residue at L293 (P = 0.0994);
MVP		0.18
MPC		0.71
ClinPred		0.13	T
GERP RS		3.4
Varity_R		0.26
gMVP		0.26

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: rs1855356004; hg19: chr11-40136970; COSMIC: COSV53422479; COSMIC: COSV53422479;