11-118262458-C-A

Variant names:

• chr11-118262458-C-A
• rs75485914
• NM_005797.4:c.416G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005797.4(MPZL2):​c.416G>T​(p.Arg139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R139Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MPZL2 NM_005797.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226
• Publications: 0 publications found

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]

MPZL2 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive 111

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: STRONG Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005797.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZL2	NM_005797.4	MANE Select	c.416G>T	p.Arg139Leu	missense	Exon 3 of 6	NP_005788.1	O60487
	MPZL2	NM_144765.3		c.416G>T	p.Arg139Leu	missense	Exon 3 of 5	NP_658911.1	O60487

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZL2	ENST00000278937.7	TSL:1 MANE Select	c.416G>T	p.Arg139Leu	missense	Exon 3 of 6	ENSP00000278937.2	O60487
	MPZL2	ENST00000438295.2	TSL:1	c.416G>T	p.Arg139Leu	missense	Exon 3 of 5	ENSP00000408362.2	O60487
	MPZL2	ENST00000887115.1		c.416G>T	p.Arg139Leu	missense	Exon 3 of 6	ENSP00000557174.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461712 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727162

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.23
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.042	D
Sift4G	Benign	0.10	T
Polyphen		0.24	B
Vest4		0.57
MutPred		0.65		Loss of sheet (P = 0.0817)
MVP		0.40
MPC		0.15
ClinPred		0.96	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.68
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs75485914; hg19: chr11-118133173;