Genetic Variant STMN3:p.Ile5Met (chr20-63653331-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015894.4(STMN3):c.15T>G(p.Ile5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 1,545,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

STMN3
NM_015894.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0470

Variant links:

Genes affected

STMN3 (HGNC:15926): (stathmin 3) This gene encodes a protein which is a member of the stathmin protein family. Members of this protein family form a complex with tubulins at a ratio of 2 tubulins for each stathmin protein. Microtubules require the ordered assembly of alpha- and beta-tubulins, and formation of a complex with stathmin disrupts microtubule formation and function. A pseudogene of this gene is located on chromosome 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

STMN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.041497648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STMN3	NM_015894.4 link	c.15T>G	p.Ile5Met	missense_variant	Exon 1 of 5	ENST00000370053.3	NP_056978.2	Q9NZ72-1
STMN3	NR_075070.2 link	n.94T>G		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STMN3	ENST00000370053.3 link	c.15T>G	p.Ile5Met	missense_variant	Exon 1 of 5	1	NM_015894.4	ENSP00000359070.1		Q9NZ72-1
STMN3	ENST00000634126.1 link	c.-15+4019T>G		intron_variant	Intron 1 of 2	3		ENSP00000488604.1		A0A0J9YXY4

Frequencies

GnomAD3 genomes

AF:

0.0000399

AC:

AN:

150384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000659

AC:

AN:

151828

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81172

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000502

AC:

AN:

1394844

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

688302

show subpopulations

Gnomad4 AFR exome

AF:

0.0000639

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000278

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000399

AC:

AN:

150384

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73356

show subpopulations

Gnomad4 AFR

AF:

0.000122

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15T>G (p.I5M) alteration is located in exon 1 (coding exon 1) of the STMN3 gene. This alteration results from a T to G substitution at nucleotide position 15, causing the isoleucine (I) at amino acid position 5 to be replaced by a methionine (M). 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

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.032

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.51

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.090

REVEL

Benign

0.049

Sift

Benign

0.061

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.056

MutPred

0.21

Loss of catalytic residue at I5 (P = 0.004);

MVP

0.16

MPC

0.82

ClinPred

0.021

GERP RS

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.075

gMVP

0.072

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over