3-152445316-G-A

Position:

• chr3-152445316-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021038.5(MBNL1):​c.584G>A​(p.Arg195Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MBNL1 NM_021038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL1	NM_021038.5	c.584G>A	p.Arg195Gln	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.584G>A	p.Arg195Gln	missense_variant	5/10	1	NM_021038.5	ENSP00000319429.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727182

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.584G>A (p.R195Q) alteration is located in exon 4 (coding exon 4) of the MBNL1 gene. This alteration results from a G to A substitution at nucleotide position 584, causing the arginine (R) at amino acid position 195 to be replaced by a glutamine (Q). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;T;.;T;.;T;.;.;.;.;.;D;.;.;.;T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D;.;.;.;.;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.3	M;.;M;.;M;.;.;.;M;M;.;M;.;M;M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.055	T;T;D;D;D;D;T;T;T;D;T;T;T;T;D;D
Polyphen		1.0	D;.;D;D;.;.;D;.;.;.;D;D;.;.;.;.
Vest4		0.81
MutPred		0.69		Loss of MoRF binding (P = 0.1171);Loss of MoRF binding (P = 0.1171);Loss of MoRF binding (P = 0.1171);.;Loss of MoRF binding (P = 0.1171);.;Loss of MoRF binding (P = 0.1171);.;Loss of MoRF binding (P = 0.1171);Loss of MoRF binding (P = 0.1171);.;Loss of MoRF binding (P = 0.1171);.;Loss of MoRF binding (P = 0.1171);Loss of MoRF binding (P = 0.1171);.;
MVP		0.82
MPC		2.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2099207634; hg19: chr3-152163105; COSMIC: COSV56826999; COSMIC: COSV56826999;