8-119208515-G-A

Position:

• chr8-119208515-G-A

Variant summary

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

The ENST00000614891.5(MAL2):​c.43G>A​(p.Ala15Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000817 in 1,224,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.2e-7 (0 hom.)
• Consequence: MAL2 ENST00000614891.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

MAL2 (HGNC:13634): (mal, T cell differentiation protein 2) This gene encodes a multispan transmembrane protein belonging to the MAL proteolipid family. The protein is a component of lipid rafts and, in polarized cells, it primarily localizes to endosomal structures beneath the apical membrane. It is required for transcytosis, an intracellular transport pathway used to deliver membrane-bound proteins and exogenous cargos from the basolateral to the apical surface. [provided by RefSeq, Jul 2008]

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=0.24528775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAL2	NM_052886.3	c.43G>A	p.Ala15Thr	missense_variant	1/4	ENST00000614891.5	NP_443118.1
MAL2	XM_011516807.3	c.43G>A	p.Ala15Thr	missense_variant	1/3		XP_011515109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAL2	ENST00000614891.5	c.43G>A	p.Ala15Thr	missense_variant	1/4	1	NM_052886.3	ENSP00000479708	P1
MAL2	ENST00000522112.6	c.-72-13072G>A		intron_variant		4		ENSP00000483044
MAL2	ENST00000534619.5	c.-73+422G>A		intron_variant		4		ENSP00000482729

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.17e-7 AC: 1 AN: 1224398 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 598786

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: 0.0000188

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 06, 2023

The c.43G>A (p.A15T) alteration is located in exon 1 (coding exon 1) of the MAL2 gene. This alteration results from a G to A substitution at nucleotide position 43, causing the alanine (A) at amino acid position 15 to be replaced by a threonine (T). 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	0.15
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.25	T
PrimateAI	Pathogenic	0.91	D
Sift4G	Benign	0.093	T
Polyphen		0.90	P
Vest4		0.17
MVP		0.39
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.66

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: rs1179836198; hg19: chr8-120220754;