Variant X-132406245-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001386889.1(MBNL3):c.325G>A(p.Ala109Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

MBNL3
NM_001386889.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.18

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08611956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL3	NM_001386889.1 linkuse as main transcript	c.325G>A	p.Ala109Thr	missense_variant	3/9	ENST00000370853.8	NP_001373818.1
RAP2C-AS1	NR_110410.1 linkuse as main transcript	n.424-23568C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBNL3	ENST00000370853.8 linkuse as main transcript	c.325G>A	p.Ala109Thr	missense_variant	3/9	1	NM_001386889.1	ENSP00000359890	A1	Q9NUK0-1
RAP2C-AS1	ENST00000441399.3 linkuse as main transcript	n.722-23568C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183106

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67650

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097914

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363342

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000238

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The c.325G>A (p.A109T) alteration is located in exon 2 (coding exon 2) of the MBNL3 gene. This alteration results from a G to A substitution at nucleotide position 325, causing the alanine (A) at amino acid position 109 to be replaced by a threonine (T). 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

0.075

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.029

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

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.086

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.045

.;.;.;N;.;N;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N;N;N

REVEL

Benign

0.039

Sift

Benign

0.38

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

Sift4G

Benign

0.47

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

Polyphen

0.14

B;.;.;B;P;B;.;.;.

Vest4

0.14

MutPred

0.13

.;.;Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;Gain of relative solvent accessibility (P = 0.005);.;.;.;

MVP

0.44

MPC

0.56

ClinPred

0.14

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.43

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