16-15004194-A-G

Variant names:

• chr16-15004194-A-G
• rs768074533
• NM_015027.4:c.250A>G

Variant summary

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

The NM_015027.4(PDXDC1):​c.250A>G​(p.Asn84Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,613,516 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 51)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: PDXDC1 NM_015027.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.48
• Publications: 0 publications found

Genes affected

PDXDC1 (HGNC:28995): (pyridoxal dependent decarboxylase domain containing 1) Enables cadherin binding activity. Predicted to be involved in carboxylic acid metabolic process. Located in Golgi apparatus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.12673545).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015027.4. 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
	PDXDC1	NM_015027.4	MANE Select	c.250A>G	p.Asn84Asp	missense	Exon 5 of 23	NP_055842.2	Q6P996-1
	PDXDC1	NM_001324019.2		c.247A>G	p.Asn83Asp	missense	Exon 5 of 23	NP_001310948.1
	PDXDC1	NM_001285447.1		c.205A>G	p.Asn69Asp	missense	Exon 5 of 23	NP_001272376.1	B4DHL7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDXDC1	ENST00000396410.9	TSL:1 MANE Select	c.250A>G	p.Asn84Asp	missense	Exon 5 of 23	ENSP00000379691.4	Q6P996-1
	PDXDC1	ENST00000569715.5	TSL:1	c.169A>G	p.Asn57Asp	missense	Exon 4 of 22	ENSP00000455070.1	Q6P996-5
	PDXDC1	ENST00000535621.6	TSL:1	c.250A>G	p.Asn84Asp	missense	Exon 5 of 17	ENSP00000437835.2	Q86XE2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152288 Hom.: 0 Cov.: 51

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251220 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461228 Hom.: 0 Cov.: 33 AF XY: 0.0000426 AC XY: 31 AN XY: 726946

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111666

Other (OTH) AF: 0.0000331 AC: 2 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152288 Hom.: 0 Cov.: 51 AF XY: 0.0000403 AC XY: 3 AN XY: 74406

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41480

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000000999201), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000959 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.036
Sift	Benign	0.17	T
Sift4G	Benign	0.18	T
Polyphen		0.0030	B
Vest4		0.46
MutPred		0.50		Loss of catalytic residue at N84 (P = 0.0271)
MVP		0.25
MPC		0.12
ClinPred		0.068	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.060
gMVP		0.41
Mutation Taster		=83/17	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: rs768074533; hg19: chr16-15098051;