chr2-69938229-C-A

Variant names:

• chr2-69938229-C-A
• rs144479868
• NM_002357.4:c.611C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002357.4(MXD1):​c.611C>A​(p.Thr204Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. T204I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MXD1 NM_002357.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

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]

ASPRV1 Gene-Disease associations (from GenCC):

• ichthyosis, lamellar, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15933377).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002357.4. 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
	MXD1	NM_002357.4	MANE Select	c.611C>A	p.Thr204Asn	missense	Exon 6 of 6	NP_002348.1	Q05195-1
	MXD1	NM_001202513.2		c.608C>A	p.Thr203Asn	missense	Exon 6 of 6	NP_001189442.1	B7ZLI7
	MXD1	NM_001202514.2		c.581C>A	p.Thr194Asn	missense	Exon 5 of 5	NP_001189443.1	Q05195-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MXD1	ENST00000264444.7	TSL:1 MANE Select	c.611C>A	p.Thr204Asn	missense	Exon 6 of 6	ENSP00000264444.2	Q05195-1
	MXD1	ENST00000540449.5	TSL:1	c.581C>A	p.Thr194Asn	missense	Exon 5 of 5	ENSP00000443935.1	Q05195-2
	MXD1	ENST00000876182.1		c.608C>A	p.Thr203Asn	missense	Exon 6 of 6	ENSP00000546241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.081
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.082		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.49
MPC		0.52
ClinPred		0.61	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.082
gMVP		0.10
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs144479868; hg19: chr2-70165361;