3-197791502-G-T

Variant names:

• chr3-197791502-G-T
• rs1730493375
• NM_001365715.1:c.224G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365715.1(LRCH3):​c.224G>T​(p.Gly75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G75E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRCH3 NM_001365715.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.19
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24142858).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365715.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH3	NM_001365715.1	MANE Select	c.224G>T	p.Gly75Val	missense	Exon 1 of 21	NP_001352644.1	Q96II8-1
	LRCH3	NM_001363887.1		c.224G>T	p.Gly75Val	missense	Exon 1 of 21	NP_001350816.1	Q96II8-2
	LRCH3	NM_001365716.1		c.224G>T	p.Gly75Val	missense	Exon 1 of 20	NP_001352645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRCH3	ENST00000425562.7	TSL:5 MANE Select	c.224G>T	p.Gly75Val	missense	Exon 1 of 21	ENSP00000393579.2	Q96II8-1
	LRCH3	ENST00000334859.8	TSL:1	c.224G>T	p.Gly75Val	missense	Exon 1 of 19	ENSP00000334375.4	Q96II8-3
	LRCH3	ENST00000428136.2	TSL:5	c.224G>T	p.Gly75Val	missense	Exon 1 of 21	ENSP00000394763.2	Q96II8-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447782 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719670

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000312 AC: 1 AN: 32010

American (AMR) AF: 0.00 AC: 0 AN: 43638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25614

East Asian (EAS) AF: 0.00 AC: 0 AN: 38524

South Asian (SAS) AF: 0.00 AC: 0 AN: 84492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107034

Other (OTH) AF: 0.00 AC: 0 AN: 59738

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.0087
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.036
Sift	Benign	0.067	T
Sift4G	Uncertain	0.050	T
Polyphen		0.71	P
Vest4		0.45
MutPred		0.37		Loss of disorder (P = 0.0325)
MVP		0.54
MPC		0.14
ClinPred		0.73	D
GERP RS		2.8
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.43
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1730493375; hg19: chr3-197518373;