chrX-132390944-G-A

Variant names:

• chrX-132390944-G-A
• rs780182461
• NM_001386889.1:c.674C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001386889.1(MBNL3):​c.674C>T​(p.Ser225Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,209,041 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: MBNL3 NM_001386889.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96
• Publications: 3 publications found

Genes affected

MBNL3 (HGNC:20564): (muscleblind like splicing regulator 3) This gene encodes a member of the muscleblind-like family of proteins. The encoded protein may function in regulation of alternative splicing and may play a role in the pathophysiology of myotonic dystrophy. Alternatively spliced transcript variants have been described. [provided by RefSeq, Dec 2009]

RAP2C-AS1 (HGNC:40957): (RAP2C antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25856078).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386889.1. 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
	MBNL3	NM_001386889.1	MANE Select	c.674C>T	p.Ser225Leu	missense	Exon 5 of 9	NP_001373818.1	Q9NUK0-1
	MBNL3	NM_001386891.1		c.674C>T	p.Ser225Leu	missense	Exon 5 of 10	NP_001373820.1
	MBNL3	NM_001386892.1		c.674C>T	p.Ser225Leu	missense	Exon 5 of 10	NP_001373821.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBNL3	ENST00000370853.8	TSL:1 MANE Select	c.674C>T	p.Ser225Leu	missense	Exon 5 of 9	ENSP00000359890.3	Q9NUK0-1
	MBNL3	ENST00000370839.7	TSL:1	c.674C>T	p.Ser225Leu	missense	Exon 4 of 9	ENSP00000359876.3	Q9NUK0-2
	MBNL3	ENST00000538204.6	TSL:1	c.524C>T	p.Ser175Leu	missense	Exon 4 of 7	ENSP00000439618.1	Q9NUK0-4

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111194 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182670 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1097847 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363253

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.0000284 AC: 1 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841820

Other (OTH) AF: 0.0000217 AC: 1 AN: 46079

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111194 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33398

African (AFR) AF: 0.00 AC: 0 AN: 30548

American (AMR) AF: 0.00 AC: 0 AN: 10424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2611

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53068

Other (OTH) AF: 0.00 AC: 0 AN: 1495

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.084
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	M
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.11
Sift	Benign	0.051	T
Sift4G	Benign	0.24	T
Polyphen		0.64	P
Vest4		0.50
MutPred		0.40		Loss of phosphorylation at S225 (P = 0.0377)
MVP		0.28
MPC		0.38
ClinPred		0.38	T
GERP RS		5.0
PromoterAI		0.0073	Neutral
Varity_R		0.30
gMVP		0.72
Mutation Taster		=52/48	polymorphism

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: rs780182461; hg19: chrX-131524972;