2-69937313-C-A

Variant names:

• chr2-69937313-C-A
• NM_002357.4:c.397C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002357.4(MXD1):​c.397C>A​(p.Leu133Met) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MXD1 NM_002357.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

Genes affected

MXD1 (HGNC:6761): (MAX dimerization protein 1) This gene encodes a member of the MYC/MAX/MAD network of basic helix-loop-helix leucine zipper transcription factors. The MYC/MAX/MAD transcription factors mediate cellular proliferation, differentiation and apoptosis. The encoded protein antagonizes MYC-mediated transcriptional activation of target genes by competing for the binding partner MAX and recruiting repressor complexes containing histone deacetylases. Mutations in this gene may play a role in acute leukemia, and the encoded protein is a potential tumor suppressor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

ASPRV1 (HGNC:26321): (aspartic peptidase retroviral like 1) Filaggrin is a structural protein that is crucial for in the development and maintenance of the skin barrier. This gene encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. Expression is found primarily in the epidermis and inner root sheath of hair follicles. [provided by RefSeq, May 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32862008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MXD1	NM_002357.4	c.397C>A	p.Leu133Met	missense_variant	Exon 5 of 6	ENST00000264444.7	NP_002348.1
MXD1	NM_001202513.2	c.397C>A	p.Leu133Met	missense_variant	Exon 5 of 6		NP_001189442.1
MXD1	NM_001202514.2	c.367C>A	p.Leu123Met	missense_variant	Exon 4 of 5		NP_001189443.1
ASPRV1	NR_170375.1	n.1101-4120G>T		intron_variant	Intron 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MXD1	ENST00000264444.7	c.397C>A	p.Leu133Met	missense_variant	Exon 5 of 6	1	NM_002357.4	ENSP00000264444.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.397C>A (p.L133M) alteration is located in exon 5 (coding exon 5) of the MXD1 gene. This alteration results from a C to A substitution at nucleotide position 397, causing the leucine (L) at amino acid position 133 to be replaced by a methionine (M). 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	0.30
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Pathogenic	3.0	.;.;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.73, 0.77
MutPred		0.32		.;.;Gain of methylation at K130 (P = 0.0572);
MVP		0.85
MPC		1.3
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-70164445; COSMIC: COSV52479598; COSMIC: COSV52479598;