12-50177398-C-T

Variant names:

• chr12-50177398-C-T
• rs1420458016
• NM_016357.5:c.1946G>A

Variant summary

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

The NM_016357.5(LIMA1):​c.1946G>A​(p.Gly649Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G649R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LIMA1 NM_016357.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.234
• Publications: 0 publications found

Genes affected

LIMA1 (HGNC:24636): (LIM domain and actin binding 1) This gene encodes a cytoskeleton-associated protein that inhibits actin filament depolymerization and cross-links filaments in bundles. It is downregulated in some cancer cell lines. Alternatively spliced transcript variants encoding different isoforms have been described for this gene, and expression of some of the variants maybe independently regulated. [provided by RefSeq, Aug 2011]

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=0.08232099).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016357.5. 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
	LIMA1	NM_016357.5	MANE Select	c.1946G>A	p.Gly649Glu	missense	Exon 11 of 11	NP_057441.1	Q9UHB6-1
	LIMA1	NM_001113546.2		c.1949G>A	p.Gly650Glu	missense	Exon 11 of 11	NP_001107018.1	Q9UHB6-4
	LIMA1	NM_001394886.1		c.1949G>A	p.Gly650Glu	missense	Exon 11 of 11	NP_001381815.1	Q9UHB6-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIMA1	ENST00000341247.9	TSL:1 MANE Select	c.1946G>A	p.Gly649Glu	missense	Exon 11 of 11	ENSP00000340184.4	Q9UHB6-1
	LIMA1	ENST00000394943.7	TSL:1	c.1949G>A	p.Gly650Glu	missense	Exon 11 of 11	ENSP00000378400.3	Q9UHB6-4
	LIMA1	ENST00000552783.5	TSL:1	c.1469G>A	p.Gly490Glu	missense	Exon 8 of 8	ENSP00000448779.1	Q9UHB6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00000736

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.76
DANN	Benign	0.86
DEOGEN2	Benign	0.0064	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.23
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.19
Sift	Benign	0.12	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.065
MutPred		0.22		Gain of sheet (P = 0.0477)
MVP		0.84
MPC		0.28
ClinPred		0.014	T
GERP RS		2.4
Varity_R		0.021
gMVP		0.10
Mutation Taster		=83/17	polymorphism

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: rs1420458016; hg19: chr12-50571181;