rs17433672

Positions:

• chr3-152268473-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000355460.6(MBNL1):​c.-1409C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0619 in 310,936 control chromosomes in the GnomAD database, including 841 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (385 hom., cov: 32)
  • Exomes 𝑓: 0.065 (456 hom.)
• Consequence: MBNL1 ENST00000355460.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.41

Genes affected

MBNL1 (HGNC:6923): (muscleblind like splicing regulator 1) This gene encodes a member of the muscleblind protein family which was initially described in Drosophila melanogaster. The encoded protein is a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Mice lacking this gene exhibited muscle abnormalities and cataracts. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. The different isoforms are thought to have different binding specificities and/or splicing activities. [provided by RefSeq, Sep 2015]

MBNL1-AS1 (HGNC:44584): (MBNL1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-152268473-C-T is Benign according to our data. Variant chr3-152268473-C-T is described in ClinVar as [Benign]. Clinvar id is 218788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL1-AS1	NR_027037.1	n.788G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBNL1	ENST00000355460.6	c.-1409C>T		5_prime_UTR_variant	1/9	1		ENSP00000347637	A1
MBNL1	ENST00000282486.10	c.-1409C>T		5_prime_UTR_variant	1/10	5		ENSP00000282486	P4
MBNL1	ENST00000282488.11	c.-1409C>T		5_prime_UTR_variant	1/11	5		ENSP00000282488	A1

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8931 AN: 152194 Hom.: 385 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0549

Gnomad AMR AF: 0.0496

Gnomad ASJ AF: 0.0334

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0219

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.0559

GnomAD4 exome AF: 0.0650 AC: 10310 AN: 158624 Hom.: 456 Cov.: 0 AF XY: 0.0586 AC XY: 5120 AN XY: 87374

Gnomad4 AFR exome AF: 0.00923

Gnomad4 AMR exome AF: 0.0463

Gnomad4 ASJ exome AF: 0.0302

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.0820

Gnomad4 OTH exome AF: 0.0674

GnomAD4 genome AF: 0.0587 AC: 8934 AN: 152312 Hom.: 385 Cov.: 32 AF XY: 0.0591 AC XY: 4400 AN XY: 74484

Gnomad4 AFR AF: 0.0150

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.0334

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0221

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0859

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0732 Hom.: 454

Bravo AF: 0.0504

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 10, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.68
DANN	Benign	0.86

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

Other links and lift over

dbSNP: rs17433672; hg19: chr3-151986262;