Genetic Variant MBNL3:c.535-8G>A (chrX-132391091-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001386889.1(MBNL3):c.535-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,160,882 control chromosomes in the GnomAD database, including 117 homozygotes. There are 1,422 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0042 ( 8 hom., 155 hem., cov: 23)

Exomes 𝑓: 0.0040 ( 109 hom. 1267 hem. )

Consequence

MBNL3
NM_001386889.1 splice_region, intron

Scores

Splicing: ADA: 0.001235

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.592

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-132391091-C-T is Benign according to our data. Variant chrX-132391091-C-T is described in ClinVar as [Benign]. Clinvar id is 771551.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBNL3	NM_001386889.1 link	c.535-8G>A		splice_region_variant, intron_variant	Intron 4 of 8	ENST00000370853.8	NP_001373818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL3	ENST00000370853.8 link	c.535-8G>A		splice_region_variant, intron_variant	Intron 4 of 8	1	NM_001386889.1	ENSP00000359890.3		Q9NUK0-1

Frequencies

GnomAD3 genomes

AF:

0.00420

AC:

469

AN:

111571

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

155

AN XY:

33753

show subpopulations

Gnomad AFR

AF:

0.000685

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0771

Gnomad SAS

AF:

0.00302

Gnomad FIN

AF:

0.000667

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000207

Gnomad OTH

AF:

0.000672

GnomAD3 exomes

AF:

0.0112

AC:

2015

AN:

179302

Hom.:

AF XY:

0.00888

AC XY:

579

AN XY:

65176

show subpopulations

Gnomad AFR exome

AF:

0.000842

Gnomad AMR exome

AF:

0.0349

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0716

Gnomad SAS exome

AF:

0.000897

Gnomad FIN exome

AF:

0.00145

Gnomad NFE exome

AF:

0.0000869

Gnomad OTH exome

AF:

0.00447

GnomAD4 exome

AF:

0.00399

AC:

4187

AN:

1049260

Hom.:

109

Cov.:

AF XY:

0.00398

AC XY:

1267

AN XY:

318728

show subpopulations

Gnomad4 AFR exome

AF:

0.000626

Gnomad4 AMR exome

AF:

0.0309

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0905

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.00107

Gnomad4 NFE exome

AF:

0.0000525

Gnomad4 OTH exome

AF:

0.00517

GnomAD4 genome

AF:

0.00420

AC:

469

AN:

111622

Hom.:

Cov.:

AF XY:

0.00458

AC XY:

155

AN XY:

33814

show subpopulations

Gnomad4 AFR

AF:

0.000683

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0774

Gnomad4 SAS

AF:

0.00302

Gnomad4 FIN

AF:

0.000667

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.000663

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.00615

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.1

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.024

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