11-118260137-T-TA

Variant names:

• chr11-118260137-T-TA
• rs1439267095
• NM_005797.4:c.500dupT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005797.4(MPZL2):​c.500dupT​(p.Ile168AsnfsTer22) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MPZL2 NM_005797.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.81

Genes affected

MPZL2 (HGNC:3496): (myelin protein zero like 2) Thymus development depends on a complex series of interactions between thymocytes and the stromal component of the organ. Epithelial V-like antigen (EVA) is expressed in thymus epithelium and strongly downregulated by thymocyte developmental progression. This gene is expressed in the thymus and in several epithelial structures early in embryogenesis. It is highly homologous to the myelin protein zero and, in thymus-derived epithelial cell lines, is poorly soluble in nonionic detergents, strongly suggesting an association to the cytoskeleton. Its capacity to mediate cell adhesion through a homophilic interaction and its selective regulation by T cell maturation might imply the participation of EVA in the earliest phases of thymus organogenesis. The protein bears a characteristic V-type domain and two potential N-glycosylation sites in the extracellular domain; a putative serine phosphorylation site for casein kinase 2 is also present in the cytoplasmic tail. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-118260137-T-TA is Pathogenic according to our data. Variant chr11-118260137-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 3601281.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZL2	NM_005797.4	c.500dupT	p.Ile168AsnfsTer22	frameshift_variant	Exon 4 of 6	ENST00000278937.7	NP_005788.1
MPZL2	NM_144765.3	c.500dupT	p.Ile168AsnfsTer22	frameshift_variant	Exon 4 of 5		NP_658911.1
MPZL2	XM_047426229.1	c.*7dupT		3_prime_UTR_variant	Exon 4 of 4		XP_047282185.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZL2	ENST00000278937.7	c.500dupT	p.Ile168AsnfsTer22	frameshift_variant	Exon 4 of 6	1	NM_005797.4	ENSP00000278937.2
MPZL2	ENST00000438295.2	c.500dupT	p.Ile168AsnfsTer22	frameshift_variant	Exon 4 of 5	1		ENSP00000408362.2
MPZL2	ENST00000529376.5	n.630dupT		non_coding_transcript_exon_variant	Exon 4 of 4	2
MPZL2	ENST00000534175.6	n.548dupT		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hearing loss, autosomal recessive 111 Pathogenic:1

Jan 09, 2025

Institute of Rare Diseases, West China Hospital, Sichuan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1;PM3_Supporting;PM2_Supporting -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1439267095; hg19: chr11-118130852;