17-57401451-T-C

Variant names:

• chr17-57401451-T-C
• NM_138962.4:c.385T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138962.4(MSI2):​c.385T>C​(p.Tyr129His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSI2 NM_138962.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

Genes affected

MSI2 (HGNC:18585): (musashi RNA binding protein 2) This gene encodes an RNA-binding protein that is a member of the Musashi protein family. The encoded protein is transcriptional regulator that targets genes involved in development and cell cycle regulation. Mutations in this gene are associated with poor prognosis in certain types of cancers. This gene has also been shown to be rearranged in certain cancer cells. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSI2	NM_138962.4	c.385T>C	p.Tyr129His	missense_variant	Exon 6 of 14	ENST00000284073.7	NP_620412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSI2	ENST00000284073.7	c.385T>C	p.Tyr129His	missense_variant	Exon 6 of 14	1	NM_138962.4	ENSP00000284073.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 30, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSI2 c.385T>C (p.Tyr129His) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a highly conserved RNA recognition motif in an alpha helix and changes a polar tyrosine to a positively charged histidine, and computational predictors indicate that the variant is damaging, evidence that correlates with impact to MSI2 function. Due to limited information, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.1	.;L;.;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.2	D;D;D;.;D;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.026	D;D;D;.;D;.
Sift4G	Uncertain	0.018	D;D;D;D;T;D
Polyphen		1.0	D;P;D;.;.;.
Vest4		0.88
MutPred		0.75		.;Gain of disorder (P = 0.0529);.;.;.;.;
MVP		0.90
MPC		2.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.95

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: chr17-55478812;