NM_021038.5:c.374C>T

Variant names:

• chr3-152432745-C-T
• NM_021038.5:c.374C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021038.5(MBNL1):​c.374C>T​(p.Ala125Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 7.19
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021038.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBNL1	NM_021038.5	MANE Select	c.374C>T	p.Ala125Val	missense	Exon 4 of 10	NP_066368.2
	MBNL1	NM_001376818.1		c.467C>T	p.Ala156Val	missense	Exon 5 of 12	NP_001363747.1
	MBNL1	NM_001376819.1		c.467C>T	p.Ala156Val	missense	Exon 6 of 13	NP_001363748.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBNL1	ENST00000324210.10	TSL:1 MANE Select	c.374C>T	p.Ala125Val	missense	Exon 4 of 10	ENSP00000319429.5	Q9NR56-5
	MBNL1	ENST00000463374.5	TSL:1	c.374C>T	p.Ala125Val	missense	Exon 3 of 9	ENSP00000418108.1	Q9NR56-1
	MBNL1	ENST00000355460.6	TSL:1	c.374C>T	p.Ala125Val	missense	Exon 4 of 9	ENSP00000347637.2	Q9NR56-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Benign	0.037	D
Sift4G	Benign	0.17	T
Polyphen		0.71	P
Vest4		0.78
MutPred		0.15		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.54
MPC		1.9
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.72
Mutation Taster		=40/60	disease causing

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

Other links and lift over

hg19: chr3-152150534;