Genetic Variant MBNL3:p.Ser225Leu (chrX-132390944-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001386889.1(MBNL3):c.674C>T(p.Ser225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,209,041 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000012 ( 0 hom. 4 hem. )

Consequence

MBNL3
NM_001386889.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

MBNL3 (HGNC:20564): (muscleblind like splicing regulator 3) This gene encodes a member of the muscleblind-like family of proteins. The encoded protein may function in regulation of alternative splicing and may play a role in the pathophysiology of myotonic dystrophy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Dec 2009]

MBNL3 links:

RAP2C-AS1 (HGNC:40957): (RAP2C antisense RNA 1)

RAP2C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25856078).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBNL3	NM_001386889.1 link	c.674C>T	p.Ser225Leu	missense_variant	Exon 5 of 9	ENST00000370853.8	NP_001373818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL3	ENST00000370853.8 link	c.674C>T	p.Ser225Leu	missense_variant	Exon 5 of 9	1	NM_001386889.1	ENSP00000359890.3		Q9NUK0-1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33398

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182670

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1097847

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363253

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

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:

0.0000119

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000270

AC:

AN:

111194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000565

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

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

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.674C>T (p.S225L) alteration is located in exon 4 (coding exon 4) of the MBNL3 gene. This alteration results from a C to T substitution at nucleotide position 674, causing the serine (S) at amino acid position 225 to be replaced by a leucine (L). 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

0.084

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

.;.;T;T;.;.;.;T;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;D;D;D;D;D;.;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.26

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.9

.;.;.;M;.;M;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.4

D;D;D;D;D;D;D;D;D;D

REVEL

Benign

0.11

Sift

Benign

0.051

T;D;T;T;D;T;D;D;T;D

Sift4G

Benign

0.24

T;D;T;T;T;T;D;D;.;.

Polyphen

0.64

P;.;.;P;P;P;.;.;.;.

Vest4

0.50

MutPred

0.40

.;.;Loss of phosphorylation at S225 (P = 0.0377);Loss of phosphorylation at S225 (P = 0.0377);.;Loss of phosphorylation at S225 (P = 0.0377);.;.;.;.;

MVP

0.28

MPC

0.38

ClinPred

0.38

GERP RS

5.0

Varity_R

0.30

gMVP

0.72

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

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