3-152432853-C-T

Variant names:

• chr3-152432853-C-T
• rs1031137705
• NM_021038.5:c.482C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021038.5(MBNL1):​c.482C>T​(p.Pro161Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: MBNL1 NM_021038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBNL1	NM_021038.5	c.482C>T	p.Pro161Leu	missense_variant	Exon 4 of 10	ENST00000324210.10	NP_066368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL1	ENST00000324210.10	c.482C>T	p.Pro161Leu	missense_variant	Exon 4 of 10	1	NM_021038.5	ENSP00000319429.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727234

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: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.482C>T (p.P161L) alteration is located in exon 3 (coding exon 3) of the MBNL1 gene. This alteration results from a C to T substitution at nucleotide position 482, causing the proline (P) at amino acid position 161 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	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;.;.;T;.;T;.;.;.;D;.;.;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;.;.;.;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M;.;M;.;.;M;.;.;M;M;M;M;M;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D;.;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.072	T;.;T;D;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;D;T;T;T;T;T;T;T;T;T;T
Polyphen		0.044	B;.;P;.;B;.;.;B;.;.;B;.;.;.
Vest4		0.51
MutPred		0.43		Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);.;.;Loss of disorder (P = 0.0138);.;Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);Loss of disorder (P = 0.0138);.;
MVP		0.76
MPC		1.0
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.73

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: rs1031137705; hg19: chr3-152150642;