3-197791502-G-A

Position:

• chr3-197791502-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365715.1(LRCH3):​c.224G>A​(p.Gly75Glu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRCH3 NM_001365715.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24875617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRCH3	NM_001365715.1	c.224G>A	p.Gly75Glu	missense_variant	1/21	ENST00000425562.7	NP_001352644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRCH3	ENST00000425562.7	c.224G>A	p.Gly75Glu	missense_variant	1/21	5	NM_001365715.1	ENSP00000393579	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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 28, 2024

The c.224G>A (p.G75E) alteration is located in exon 1 (coding exon 1) of the LRCH3 gene. This alteration results from a G to A substitution at nucleotide position 224, causing the glycine (G) at amino acid position 75 to be replaced by a glutamic acid (E). 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	0.52
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;.;.;T;.;T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;.;L;L
MutationTaster	Benign	0.90	N;N;N;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;.;N;N;N;N
REVEL	Benign	0.055
Sift	Benign	0.046	D;.;D;D;D;T
Sift4G	Uncertain	0.038	D;.;D;T;T;T
Polyphen		0.83	P;P;.;P;B;.
Vest4		0.40
MutPred		0.36		Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);Loss of MoRF binding (P = 0.0567);
MVP		0.45
MPC		0.14
ClinPred		0.87	D
GERP RS		2.8
Varity_R		0.46
gMVP		0.36

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: rs1730493375; hg19: chr3-197518373;