chr3-152445526-C-A

Position:

• chr3-152445526-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021038.5(MBNL1):​c.794C>A​(p.Thr265Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MBNL1 NM_021038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

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 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=0.25281012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL1	NM_021038.5	c.794C>A	p.Thr265Asn	missense_variant	5/10	ENST00000324210.10	NP_066368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBNL1	ENST00000324210.10	c.794C>A	p.Thr265Asn	missense_variant	5/10	1	NM_021038.5	ENSP00000319429	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.794C>A (p.T265N) alteration is located in exon 4 (coding exon 4) of the MBNL1 gene. This alteration results from a C to A substitution at nucleotide position 794, causing the threonine (T) at amino acid position 265 to be replaced by an asparagine (N). 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	0.22
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T;T;.;T;.;.;.;.;.;.;T;.;.;.;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;T;D;T;D;T;T;T;D;.;.;.;.;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;M;.;M;.;.;M;M;.;M;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.031	D;.;T;D;T;T;T;T;T;T;D;T;T;T;T
Sift4G	Uncertain	0.013	D;D;T;T;T;D;T;T;T;T;D;T;T;T;T
Polyphen		0.077	B;.;B;B;.;B;.;.;.;B;B;.;.;.;.
Vest4		0.61
MutPred		0.26		Loss of glycosylation at T265 (P = 0.0255);Loss of glycosylation at T265 (P = 0.0255);Loss of glycosylation at T265 (P = 0.0255);.;Loss of glycosylation at T265 (P = 0.0255);Loss of glycosylation at T265 (P = 0.0255);.;Loss of glycosylation at T265 (P = 0.0255);Loss of glycosylation at T265 (P = 0.0255);.;Loss of glycosylation at T265 (P = 0.0255);.;Loss of glycosylation at T265 (P = 0.0255);Loss of glycosylation at T265 (P = 0.0255);.;
MVP		0.37
MPC		1.4
ClinPred		0.81	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-152163315;