4-41360899-C-G

Position:

• chr4-41360899-C-G

Variant summary

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

The ENST00000313860.12(LIMCH1):​c.59C>G​(p.Pro20Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000765 in 1,437,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: LIMCH1 ENST00000313860.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

Genes affected

LIMCH1 (HGNC:29191): (LIM and calponin homology domains 1) Enables myosin II head/neck binding activity. Involved in several processes, including cytoplasmic actin-based contraction involved in cell motility; positive regulation of stress fiber assembly; and regulation of focal adhesion assembly. Located in stress fiber. Colocalizes with myosin II complex. [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=0.13742277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIMCH1	NM_001330787.2	c.59C>G	p.Pro20Arg	missense_variant	1/27
LIMCH1	NM_014988.5	c.59C>G	p.Pro20Arg	missense_variant	1/27
LIMCH1	NM_001330790.2	c.59C>G	p.Pro20Arg	missense_variant	1/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIMCH1	ENST00000313860.12	c.59C>G	p.Pro20Arg	missense_variant	1/27	1		P3
LIMCH1	ENST00000512820.5	c.59C>G	p.Pro20Arg	missense_variant	1/26	1
LIMCH1	ENST00000512946.5	c.59C>G	p.Pro20Arg	missense_variant	1/26	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000765 AC: 11 AN: 1437182 Hom.: 0 Cov.: 30 AF XY: 0.00000561 AC XY: 4 AN XY: 712954

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000725

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 21, 2022

The c.59C>G (p.P20R) alteration is located in exon 1 (coding exon 1) of the LIMCH1 gene. This alteration results from a C to G substitution at nucleotide position 59, causing the proline (P) at amino acid position 20 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	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;.;L
MutationTaster	Benign	0.69	D;D;D;D;D;D;D
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.052	T;T;D;T;T
Sift4G	Uncertain	0.019	D;D;D;D;D
Polyphen		0.34, 0.23	.;B;B;B;B
Vest4		0.26
MutPred		0.28		Loss of glycosylation at P20 (P = 0.0016);Loss of glycosylation at P20 (P = 0.0016);Loss of glycosylation at P20 (P = 0.0016);Loss of glycosylation at P20 (P = 0.0016);Loss of glycosylation at P20 (P = 0.0016);
MVP		0.12
MPC		0.16
ClinPred		0.48	T
GERP RS		2.5
Varity_R		0.046

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.

Other links and lift over

hg19: chr4-41362916;