Variant 6-33795604-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002418.3(MLN):c.236T>C(p.Leu79Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000428 in 1,402,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

MLN
NM_002418.3 missense, splice_region

Scores

Splicing: ADA: 0.7573

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.73

Variant links:

Genes affected

MLN (HGNC:7141): (motilin) This gene encodes a small peptide hormone that is secreted by cells of the small intestine to regulate gastrointestinal contractions and motility. Proteolytic processing of the secreted protein produces the mature peptide and a byproduct referred to as motilin-associated peptide (MAP). Three transcript variants encoding different preproprotein isoforms but the same mature peptide have been found for this gene. [provided by RefSeq, May 2010]

MLN links:

LOC105375024 (HGNC:):

LOC105375024 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLN	NM_002418.3 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5	ENST00000430124.7	NP_002409.1	P12872-1
MLN	NM_001040109.2 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5		NP_001035198.1	P12872-3
MLN	NM_001184698.2 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5		NP_001171627.1	P12872-2
LOC105375024	XR_926707.3 linkuse as main transcript	n.3778+2449A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MLN	ENST00000430124.7 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5	1	NM_002418.3	ENSP00000388825.2	P12872-1
MLN	ENST00000507738.1 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5	1		ENSP00000425467.1	P12872-2
MLN	ENST00000266003.9 linkuse as main transcript	c.236T>C	p.Leu79Pro	missense_variant, splice_region_variant	4/5	5		ENSP00000266003.5	P12872-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000428

AC:

AN:

1402774

Hom.:

Cov.:

AF XY:

0.00000578

AC XY:

AN XY:

692136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000555

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2024

The c.236T>C (p.L79P) alteration is located in exon 4 (coding exon 3) of the MLN gene. This alteration results from a T to C substitution at nucleotide position 236, causing the leucine (L) at amino acid position 79 to be replaced by a proline (P). 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

0.29

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.079

T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.80

Gain of relative solvent accessibility (P = 0.0027);Gain of relative solvent accessibility (P = 0.0027);Gain of relative solvent accessibility (P = 0.0027);

MVP

0.34

MPC

1.1

ClinPred

1.0

GERP RS

5.5

Varity_R

0.97

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.76

dbscSNV1_RF

Benign

0.36

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over