12-50177605-C-G

Variant names:

• chr12-50177605-C-G
• rs772821365
• NM_016357.5:c.1739G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016357.5(LIMA1):​c.1739G>C​(p.Arg580Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R580Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LIMA1 NM_016357.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39946526).

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.1739G>C	p.Arg580Pro	missense	Exon 11 of 11	NP_057441.1	Q9UHB6-1
	LIMA1	NM_001113546.2		c.1742G>C	p.Arg581Pro	missense	Exon 11 of 11	NP_001107018.1	Q9UHB6-4
	LIMA1	NM_001394886.1		c.1742G>C	p.Arg581Pro	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.1739G>C	p.Arg580Pro	missense	Exon 11 of 11	ENSP00000340184.4	Q9UHB6-1
	LIMA1	ENST00000394943.7	TSL:1	c.1742G>C	p.Arg581Pro	missense	Exon 11 of 11	ENSP00000378400.3	Q9UHB6-4
	LIMA1	ENST00000552783.5	TSL:1	c.1262G>C	p.Arg421Pro	missense	Exon 8 of 8	ENSP00000448779.1	Q9UHB6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458150 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725132

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

African (AFR) AF: 0.00 AC: 0 AN: 33234

American (AMR) AF: 0.00 AC: 0 AN: 44036

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110448

Other (OTH) AF: 0.00 AC: 0 AN: 60186

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.40	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		3.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.33		Loss of MoRF binding (P = 0.0072)
MVP		0.96
MPC		0.99
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.40
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: rs772821365; hg19: chr12-50571388; COSMIC: COSV57964750; COSMIC: COSV57964750;