Genetic Variant MAL:p.Thr21Ile (chr2-95025854-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002371.4(MAL):c.62C>T(p.Thr21Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAL
NM_002371.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11

Publications

0 publications found

Variant links:

Genes affected

MAL (HGNC:6817): (mal, T cell differentiation protein) The protein encoded by this gene is a highly hydrophobic integral membrane protein belonging to the MAL family of proteolipids. The protein has been localized to the endoplasmic reticulum of T-cells and is a candidate linker protein in T-cell signal transduction. In addition, this proteolipid is localized in compact myelin of cells in the nervous system and has been implicated in myelin biogenesis and/or function. The protein plays a role in the formation, stabilization and maintenance of glycosphingolipid-enriched membrane microdomains. Down-regulation of this gene has been associated with a variety of human epithelial malignancies. Alternative splicing produces four transcript variants which vary from each other by the presence or absence of alternatively spliced exons 2 and 3. [provided by RefSeq, May 2012]

MAL links:

MAL-AS1 (HGNC:40355):

MAL-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002371.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAL	NM_002371.4	MANE Select	c.62C>T	p.Thr21Ile	missense	Exon 1 of 4	NP_002362.1	P21145-1
MAL	NM_022438.3		c.62C>T	p.Thr21Ile	missense	Exon 1 of 3	NP_071883.1	P21145-2
MAL	NM_022439.3		c.62C>T	p.Thr21Ile	missense	Exon 1 of 3	NP_071884.1	P21145-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAL	ENST00000309988.9	TSL:1 MANE Select	c.62C>T	p.Thr21Ile	missense	Exon 1 of 4	ENSP00000310880.4	P21145-1
MAL	ENST00000353004.7	TSL:1	c.62C>T	p.Thr21Ile	missense	Exon 1 of 3	ENSP00000306568.4	P21145-2
MAL	ENST00000354078.7	TSL:1	c.62C>T	p.Thr21Ile	missense	Exon 1 of 3	ENSP00000304924.3	P21145-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706424

African (AFR)

AF:

0.00

AC:

AN:

31990

American (AMR)

AF:

0.00

AC:

AN:

40164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25470

East Asian (EAS)

AF:

0.00

AC:

AN:

36982

South Asian (SAS)

AF:

0.00

AC:

AN:

80366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094608

Other (OTH)

AF:

0.00

AC:

AN:

58912

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

-0.24

MutationAssessor

Uncertain

2.9

PhyloP100

2.1

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.24

Sift

Benign

0.042

Sift4G

Uncertain

0.041

Polyphen

0.99

Vest4

0.71

MutPred

0.83

Loss of glycosylation at T20 (P = 0.0829)

MVP

0.40

MPC

0.65

ClinPred

0.99

GERP RS

4.0

PromoterAI

0.15

Neutral

(source)

Varity_R

0.42

gMVP

0.85

Mutation Taster

=47/53

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over