6-132297863-C-T

Variant names:

• chr6-132297863-C-T
• rs1774445006
• NM_015529.4:c.1601G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015529.4(MOXD1):​c.1601G>A​(p.Gly534Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MOXD1 NM_015529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.70

Genes affected

MOXD1 (HGNC:21063): (monooxygenase DBH like 1) Predicted to enable copper ion binding activity and dopamine beta-monooxygenase activity. Predicted to be involved in dopamine catabolic process; norepinephrine biosynthetic process; and octopamine biosynthetic process. Part of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MOXD1	NM_015529.4	c.1601G>A	p.Gly534Asp	missense_variant	Exon 11 of 12	ENST00000367963.8	NP_056344.2
MOXD1	XM_017010714.3	c.1496G>A	p.Gly499Asp	missense_variant	Exon 11 of 12		XP_016866203.1
MOXD1	XM_047418621.1	c.1340G>A	p.Gly447Asp	missense_variant	Exon 11 of 12		XP_047274577.1
MOXD1	XM_047418622.1	c.1340G>A	p.Gly447Asp	missense_variant	Exon 11 of 12		XP_047274578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MOXD1	ENST00000367963.8	c.1601G>A	p.Gly534Asp	missense_variant	Exon 11 of 12	1	NM_015529.4	ENSP00000356940.3
MOXD1	ENST00000336749.3	c.1397G>A	p.Gly466Asp	missense_variant	Exon 10 of 11	1		ENSP00000336998.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461228 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1601G>A (p.G534D) alteration is located in exon 11 (coding exon 11) of the MOXD1 gene. This alteration results from a G to A substitution at nucleotide position 1601, causing the glycine (G) at amino acid position 534 to be replaced by an aspartic acid (D). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.29
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.46		Loss of helix (P = 0.0068);.;
MVP		0.54
MPC		0.25
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.45
gMVP		0.90

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: rs1774445006; hg19: chr6-132619002;