X-132392325-G-C

Variant names:

• chrX-132392325-G-C
• rs768543470
• NM_001386889.1:c.352C>G

Variant summary

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

The NM_001386916.1(MBNL3):​c.-3C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000037 in 1,081,256 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: MBNL3 NM_001386916.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.98

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

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=0.17753235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBNL3	NM_001386889.1	c.352C>G	p.Pro118Ala	missense_variant	Exon 4 of 9	ENST00000370853.8	NP_001373818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBNL3	ENST00000370853.8	c.352C>G	p.Pro118Ala	missense_variant	Exon 4 of 9	1	NM_001386889.1	ENSP00000359890.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000300 AC: 5 AN: 166808 Hom.: 0 AF XY: 0.0000187 AC XY: 1 AN XY: 53554

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000370 AC: 4 AN: 1081256 Hom.: 0 Cov.: 28 AF XY: 0.00000287 AC XY: 1 AN XY: 348572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000121

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352C>G (p.P118A) alteration is located in exon 3 (coding exon 3) of the MBNL3 gene. This alteration results from a C to G substitution at nucleotide position 352, causing the proline (P) at amino acid position 118 to be replaced by an alanine (A). 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	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	.;.;T;T;.;.;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	.;.;.;M;.;M;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.016	D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;T;D;D;D;.;.
Polyphen		0.32	B;.;.;P;P;P;.;.;.
Vest4		0.60
MutPred		0.21		.;.;Loss of phosphorylation at T120 (P = 0.1344);Loss of phosphorylation at T120 (P = 0.1344);.;Loss of phosphorylation at T120 (P = 0.1344);.;.;.;
MVP		0.33
MPC		0.67
ClinPred		0.27	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs768543470; hg19: chrX-131526353;