Variant chr13-46553471-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001164211.2(LRCH1):c.75T>G(p.His25Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,547,876 control chromosomes in the GnomAD database, including 2 homozygotes. 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: 𝑓 0.00033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 1 hom. )

Consequence

LRCH1
NM_001164211.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.954

Variant links:

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]

LRCH1 links:

LRCH1 (HGNC:):

LRCH1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059411973).

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH1	NM_001164211.2 linkuse as main transcript	c.75T>G	p.His25Gln	missense_variant	1/20	ENST00000389797.8	NP_001157683.2	Q9Y2L9-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LRCH1	ENST00000389797.8 linkuse as main transcript	c.75T>G	p.His25Gln	missense_variant	1/20	1	NM_001164211.2	ENSP00000374447.3	Q9Y2L9-3
LRCH1	ENST00000389798.7 linkuse as main transcript	c.75T>G	p.His25Gln	missense_variant	1/19	1		ENSP00000374448.3	Q9Y2L9-1
LRCH1	ENST00000311191.10 linkuse as main transcript	c.75T>G	p.His25Gln	missense_variant	1/19	1		ENSP00000308493.5	Q9Y2L9-2
LRCH1	ENST00000443945.6 linkuse as main transcript	n.302T>G		non_coding_transcript_exon_variant	1/13	1

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

150860

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000421

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000531

Gnomad OTH

AF:

0.000963

GnomAD3 exomes

AF:

0.000376

AC:

AN:

151430

Hom.:

AF XY:

0.000387

AC XY:

AN XY:

80122

show subpopulations

Gnomad AFR exome

AF:

0.000372

Gnomad AMR exome

AF:

0.000327

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000353

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000610

Gnomad OTH exome

AF:

0.000698

GnomAD4 exome

AF:

0.000611

AC:

853

AN:

1396904

Hom.:

Cov.:

AF XY:

0.000611

AC XY:

421

AN XY:

688846

show subpopulations

Gnomad4 AFR exome

AF:

0.000223

Gnomad4 AMR exome

AF:

0.000394

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000240

Gnomad4 FIN exome

AF:

0.0000207

Gnomad4 NFE exome

AF:

0.000725

Gnomad4 OTH exome

AF:

0.000466

GnomAD4 genome

AF:

0.000331

AC:

AN:

150972

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

AN XY:

73768

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.000329

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000421

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000531

Gnomad4 OTH

AF:

0.000953

Alfa

AF:

0.000504

Hom.:

Bravo

AF:

0.000344

ESP6500AA

AF:

0.000267

AC:

ESP6500EA

AF:

0.000277

AC:

ExAC

AF:

0.000118

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

The c.75T>G (p.H25Q) alteration is located in exon 1 (coding exon 1) of the LRCH1 gene. This alteration results from a T to G substitution at nucleotide position 75, causing the histidine (H) at amino acid position 25 to be replaced by a glutamine (Q). 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

0.14

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0048

.;T;.

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.54

T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.39

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.45

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.22

MutPred

0.30

Gain of catalytic residue at L23 (P = 2e-04);Gain of catalytic residue at L23 (P = 2e-04);Gain of catalytic residue at L23 (P = 2e-04);

MVP

0.54

MPC

0.24

ClinPred

0.061

GERP RS

-2.9

Varity_R

0.054

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over