3-197791495-C-A

Variant names:

• chr3-197791495-C-A
• rs750518494
• NM_001365715.1:c.217C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365715.1(LRCH3):​c.217C>A​(p.Pro73Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,447,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P73S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRCH3 NM_001365715.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.91
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.831

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.217C>A	p.Pro73Thr	missense	Exon 1 of 21	NP_001352644.1	Q96II8-1
	LRCH3	NM_001363887.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 21	NP_001350816.1	Q96II8-2
	LRCH3	NM_001365716.1		c.217C>A	p.Pro73Thr	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.217C>A	p.Pro73Thr	missense	Exon 1 of 21	ENSP00000393579.2	Q96II8-1
	LRCH3	ENST00000334859.8	TSL:1	c.217C>A	p.Pro73Thr	missense	Exon 1 of 19	ENSP00000334375.4	Q96II8-3
	LRCH3	ENST00000428136.2	TSL:5	c.217C>A	p.Pro73Thr	missense	Exon 1 of 21	ENSP00000394763.2	Q96II8-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000906 AC: 2 AN: 220772 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447902 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719768

African (AFR) AF: 0.00 AC: 0 AN: 32042

American (AMR) AF: 0.00 AC: 0 AN: 43572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25622

East Asian (EAS) AF: 0.00 AC: 0 AN: 38508

South Asian (SAS) AF: 0.00 AC: 0 AN: 84500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107066

Other (OTH) AF: 0.00 AC: 0 AN: 59734

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.47		Gain of phosphorylation at P73 (P = 0.0367)
MVP		0.84
MPC		0.52
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.60
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs750518494; hg19: chr3-197518366;