chr3-152445307-A-G

Position:

• chr3-152445307-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_021038.5(MBNL1):​c.575A>G​(p.Asn192Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,768 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: 0.0000068 (0 hom.)
• Consequence: MBNL1 NM_021038.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.30

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBNL1	NM_021038.5	c.575A>G	p.Asn192Ser	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.575A>G	p.Asn192Ser	missense_variant	5/10	1	NM_021038.5	ENSP00000319429.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Aug 05, 2024

The c.575A>G (p.N192S) alteration is located in exon 4 (coding exon 4) of the MBNL1 gene. This alteration results from a A to G substitution at nucleotide position 575, causing the asparagine (N) at amino acid position 192 to be replaced by a serine (S). 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;T;.;T;.;.;.;.;.;T;.;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;.;.;.;.;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.97	L;.;L;.;L;.;.;.;L;L;.;L;.;L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.0	N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.12	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.13	B;.;B;B;.;.;B;.;.;.;D;B;.;.;.;.
Vest4		0.34
MutPred		0.54		Loss of catalytic residue at N192 (P = 0.0215);Loss of catalytic residue at N192 (P = 0.0215);Loss of catalytic residue at N192 (P = 0.0215);.;Loss of catalytic residue at N192 (P = 0.0215);.;Loss of catalytic residue at N192 (P = 0.0215);.;Loss of catalytic residue at N192 (P = 0.0215);Loss of catalytic residue at N192 (P = 0.0215);.;Loss of catalytic residue at N192 (P = 0.0215);.;Loss of catalytic residue at N192 (P = 0.0215);Loss of catalytic residue at N192 (P = 0.0215);.;
MVP		0.62
MPC		0.84
ClinPred		0.86	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.53

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: rs1331248232; hg19: chr3-152163096;