NM_021038.5:c.482C>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

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

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.482C>T	p.Pro161Leu	missense	Exon 4 of 10	NP_066368.2
	MBNL1	NM_001376818.1		c.575C>T	p.Pro192Leu	missense	Exon 5 of 12	NP_001363747.1
	MBNL1	NM_001376819.1		c.575C>T	p.Pro192Leu	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.482C>T	p.Pro161Leu	missense	Exon 4 of 10	ENSP00000319429.5	Q9NR56-5
	MBNL1	ENST00000463374.5	TSL:1	c.482C>T	p.Pro161Leu	missense	Exon 3 of 9	ENSP00000418108.1	Q9NR56-1
	MBNL1	ENST00000355460.6	TSL:1	c.482C>T	p.Pro161Leu	missense	Exon 4 of 9	ENSP00000347637.2	Q9NR56-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251462 AF XY: 0.00000736

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.24
Sift	Benign	0.072	T
Sift4G	Benign	0.60	T
Polyphen		0.044	B
Vest4		0.51
MutPred		0.43		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
Mutation Taster		=26/74	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

dbSNP: rs1031137705; hg19: chr3-152150642; COSMIC: COSV108759054;