Genetic Variant LRCH3:p.Cys148Arg (chr3-197817210-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001365715.1(LRCH3):c.442T>C(p.Cys148Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

LRCH3
NM_001365715.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.60

Variant links:

Genes affected

LRCH3 (HGNC:28637): (leucine rich repeats and calponin homology domain containing 3) Involved in septin cytoskeleton organization. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

LRCH3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRCH3	NM_001365715.1 link	c.442T>C	p.Cys148Arg	missense_variant	Exon 3 of 21	ENST00000425562.7	NP_001352644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRCH3	ENST00000425562.7 link	c.442T>C	p.Cys148Arg	missense_variant	Exon 3 of 21	5	NM_001365715.1	ENSP00000393579.2		Q96II8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723702

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.442T>C (p.C148R) alteration is located in exon 3 (coding exon 3) of the LRCH3 gene. This alteration results from a T to C substitution at nucleotide position 442, causing the cysteine (C) at amino acid position 148 to be replaced by an arginine (R). 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

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;.;.;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;D

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L;L;L;L

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-9.2

D;.;D;D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Uncertain

0.0060

D;.;D;D;D

Polyphen

1.0

D;D;.;D;.

Vest4

0.80

MutPred

0.68

Gain of methylation at C148 (P = 0.0334);Gain of methylation at C148 (P = 0.0334);Gain of methylation at C148 (P = 0.0334);Gain of methylation at C148 (P = 0.0334);Gain of methylation at C148 (P = 0.0334);

MVP

0.54

MPC

0.69

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.76

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over