2-95049590-T-C

Position:

chr2-95049590-T-C

Variant summary

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

The NM_002371.4(MAL):c.271T>C(p.Tyr91His) variant causes a missense change. The variant allele was found at a frequency of 0.000428 in 1,614,066 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 1 hom. )

Consequence

MAL
NM_002371.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.72

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAL	NM_002371.4 linkuse as main transcript	c.271T>C	p.Tyr91His	missense_variant	3/4	ENST00000309988.9	NP_002362.1
MAL	NM_022439.3 linkuse as main transcript	c.103T>C	p.Tyr35His	missense_variant	2/3		NP_071884.1
MAL	NM_022438.3 linkuse as main transcript	c.261+1464T>C		intron_variant			NP_071883.1
MAL	NM_022440.3 linkuse as main transcript	c.94-3791T>C		intron_variant			NP_071885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAL	ENST00000309988.9 linkuse as main transcript	c.271T>C	p.Tyr91His	missense_variant	3/4	1	NM_002371.4	ENSP00000310880	P1	P21145-1
MAL	ENST00000354078.7 linkuse as main transcript	c.103T>C	p.Tyr35His	missense_variant	2/3	1		ENSP00000304924		P21145-3
MAL	ENST00000349807.3 linkuse as main transcript	c.94-3791T>C		intron_variant		1		ENSP00000322860		P21145-4
MAL	ENST00000353004.7 linkuse as main transcript	c.261+1464T>C		intron_variant		1		ENSP00000306568		P21145-2

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000514

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000251

AC:

AN:

251222

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135762

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000434

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:

0.000379

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000436

AC:

638

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

293

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000534

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000348

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000514

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000423

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

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

Apr 16, 2024

The c.271T>C (p.Y91H) alteration is located in exon 3 (coding exon 3) of the MAL gene. This alteration results from a T to C substitution at nucleotide position 271, causing the tyrosine (Y) at amino acid position 91 to be replaced by a histidine (H). 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

Pathogenic

0.83

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.049

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.3

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-4.2

D;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.022

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.61

MVP

0.39

MPC

0.75

ClinPred

0.67

GERP RS

5.6

Varity_R

0.28

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over