12-120357820-T-C

Variant names:

• chr12-120357820-T-C
• rs199511098
• NM_002442.4:c.530A>G

Variant summary

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

The NM_002442.4(MSI1):​c.530A>G​(p.Lys177Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. K177T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSI1 NM_002442.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

Genes affected

MSI1 (HGNC:7330): (musashi RNA binding protein 1) This gene encodes a protein containing two conserved tandem RNA recognition motifs. Similar proteins in other species function as RNA-binding proteins and play central roles in posttranscriptional gene regulation. Expression of this gene has been correlated with the grade of the malignancy and proliferative activity in gliomas and melanomas. A pseudogene for this gene is located on chromosome 11q13. [provided by RefSeq, Jul 2008]

MSI1 Gene-Disease associations (from GenCC):

• microcephaly

  Inheritance: AR Classification: LIMITED Submitted by: G2P

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, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002442.4. 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
	MSI1	NM_002442.4	MANE Select	c.530A>G	p.Lys177Arg	missense	Exon 8 of 15	NP_002433.1	O43347
	MSI1	NM_001414485.1		c.527A>G	p.Lys176Arg	missense	Exon 8 of 15	NP_001401414.1
	MSI1	NM_001414486.1		c.530A>G	p.Lys177Arg	missense	Exon 8 of 15	NP_001401415.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSI1	ENST00000257552.7	TSL:1 MANE Select	c.530A>G	p.Lys177Arg	missense	Exon 8 of 15	ENSP00000257552.2	O43347
	MSI1	ENST00000923996.1		c.530A>G	p.Lys177Arg	missense	Exon 8 of 16	ENSP00000594055.1
	MSI1	ENST00000854931.1		c.530A>G	p.Lys177Arg	missense	Exon 8 of 15	ENSP00000524990.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.94	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.035	D
Polyphen		0.97	D
Vest4		0.76
MutPred		0.44		Gain of catalytic residue at K177 (P = 0.007)
MVP		0.73
MPC		1.8
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.67
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: rs199511098; hg19: chr12-120795623;