2-69933526-T-C

Variant names:

• chr2-69933526-T-C
• rs897119
• NM_002357.4:c.204-1825T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002357.4(MXD1):​c.204-1825T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 152,008 control chromosomes in the GnomAD database, including 23,756 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23756 hom., cov: 32)
• Consequence: MXD1 NM_002357.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.518
• Publications: 8 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: STRONG, MODERATE Submitted by: PanelApp Australia, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MXD1	NM_002357.4	c.204-1825T>C		intron_variant	Intron 3 of 5	ENST00000264444.7	NP_002348.1
MXD1	NM_001202513.2	c.204-1825T>C		intron_variant	Intron 3 of 5		NP_001189442.1
MXD1	NM_001202514.2	c.174-1825T>C		intron_variant	Intron 2 of 4		NP_001189443.1
ASPRV1	NR_170375.1	n.1101-333A>G		intron_variant	Intron 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MXD1	ENST00000264444.7	c.204-1825T>C		intron_variant	Intron 3 of 5	1	NM_002357.4	ENSP00000264444.2
MXD1	ENST00000540449.5	c.174-1825T>C		intron_variant	Intron 2 of 4	1		ENSP00000443935.1
MXD1	ENST00000435990.5	c.108-1825T>C		intron_variant	Intron 5 of 7	3		ENSP00000410672.1
MXD1	ENST00000409442.2	n.78-1825T>C		intron_variant	Intron 2 of 4	2		ENSP00000386523.2

Frequencies

GnomAD3 genomes AF: 0.535 AC: 81282 AN: 151890 Hom.: 23718 Cov.: 32

Gnomad AFR AF: 0.785

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.472

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.535 AC: 81364 AN: 152008 Hom.: 23756 Cov.: 32 AF XY: 0.536 AC XY: 39795 AN XY: 74294

African (AFR) AF: 0.785 AC: 32562 AN: 41460

American (AMR) AF: 0.428 AC: 6539 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1416 AN: 3472

East Asian (EAS) AF: 0.556 AC: 2867 AN: 5154

South Asian (SAS) AF: 0.483 AC: 2327 AN: 4820

European-Finnish (FIN) AF: 0.482 AC: 5086 AN: 10552

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.429 AC: 29126 AN: 67956

Other (OTH) AF: 0.469 AC: 991 AN: 2112

Alfa AF: 0.486 Hom.: 3025

Bravo AF: 0.540

Asia WGS AF: 0.549 AC: 1907 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.3
DANN	Benign	0.55
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs897119; hg19: chr2-70160658;