13-46681793-A-T

Position:

• chr13-46681793-A-T

Variant summary

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

The NM_001164211.2(LRCH1):​c.632A>T​(p.Lys211Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,646 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LRCH1 NM_001164211.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82

Genes affected

LRCH1 (HGNC:20309): (leucine rich repeats and calponin homology domain containing 1) This gene encodes a protein with a leucine-rich repeat and a calponin homology domain. Polymorphism in this gene may be associated with susceptibililty to knee osteoarthritis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40485033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH1	NM_001164211.2	c.632A>T	p.Lys211Ile	missense_variant	4/20	ENST00000389797.8	NP_001157683.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH1	ENST00000389797.8	c.632A>T	p.Lys211Ile	missense_variant	4/20	1	NM_001164211.2	ENSP00000374447

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461646 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727154

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 07, 2023

The c.632A>T (p.K211I) alteration is located in exon 4 (coding exon 4) of the LRCH1 gene. This alteration results from a A to T substitution at nucleotide position 632, causing the lysine (K) at amino acid position 211 to be replaced by an isoleucine (I). 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	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.27
Sift	Benign	0.074	T;D;T
Sift4G	Uncertain	0.059	T;D;T
Polyphen		1.0	D;B;.
Vest4		0.47
MutPred		0.47		Gain of catalytic residue at I207 (P = 0.0048);Gain of catalytic residue at I207 (P = 0.0048);Gain of catalytic residue at I207 (P = 0.0048);
MVP		0.31
MPC		1.1
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.39
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1369564312; hg19: chr13-47255928;