5-177307873-C-G

Position:

• chr5-177307873-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031300.4(MXD3):​c.413G>C​(p.Arg138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MXD3 NM_031300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.397

Genes affected

MXD3 (HGNC:14008): (MAX dimerization protein 3) This gene encodes a member of the Myc superfamily of basic helix-loop-helix leucine zipper transcriptional regulators. The encoded protein forms a heterodimer with the cofactor MAX which binds specific E-box DNA motifs in the promoters of target genes and regulates their transcription. Disruption of the MAX-MXD3 complex is associated with uncontrolled cell proliferation and tumorigenesis. Transcript variants of this gene encoding different isoforms have been described.[provided by RefSeq, Dec 2008]

MXD3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13193771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MXD3	NM_031300.4	c.413G>C	p.Arg138Pro	missense_variant	5/6	ENST00000439742.7	NP_112590.1
MXD3	NM_001394986.1	c.413G>C	p.Arg138Pro	missense_variant	6/7		NP_001381915.1
MXD3	NM_001394987.1	c.383G>C	p.Arg128Pro	missense_variant	4/5		NP_001381916.1
MXD3	NM_001142935.2	c.413G>C	p.Arg138Pro	missense_variant	5/6		NP_001136407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MXD3	ENST00000439742.7	c.413G>C	p.Arg138Pro	missense_variant	5/6	1	NM_031300.4	ENSP00000401867.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455642 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 723796

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.413G>C (p.R138P) alteration is located in exon 5 (coding exon 5) of the MXD3 gene. This alteration results from a G to C substitution at nucleotide position 413, causing the arginine (R) at amino acid position 138 to be replaced by a proline (P). 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	0.20
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.24	.;.;T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.86	D;D;.;T;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.7	L;L;L;L;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.030	D;D;D;D;D
Sift4G	Benign	0.095	T;D;T;T;.
Polyphen		0.0030	B;.;B;B;.
Vest4		0.57
MutPred		0.27		Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);Loss of MoRF binding (P = 6e-04);.;
MVP		0.82
MPC		0.45
ClinPred		0.064	T
GERP RS		0.48
Varity_R		0.29
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs763951745; hg19: chr5-176734874;