6-3751490-C-A

Position:

• chr6-3751490-C-A

Variant summary

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

The NM_183373.4(PXDC1):​c.42G>T​(p.Met14Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,452,092 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: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PXDC1 NM_183373.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.59

Genes affected

PXDC1 (HGNC:21361): (PX domain containing 1) Predicted to enable phosphatidylinositol binding activity. [provided by Alliance of Genome Resources, Apr 2022]

PXDC1 (HGNC:):

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, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXDC1	NM_183373.4	c.42G>T	p.Met14Ile	missense_variant	1/5	ENST00000380283.5	NP_899229.2
PXDC1	XR_007059222.1	n.224G>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXDC1	ENST00000380283.5	c.42G>T	p.Met14Ile	missense_variant	1/5	1	NM_183373.4	ENSP00000369636.5
PXDC1	ENST00000477592.2	n.43G>T		non_coding_transcript_exon_variant	1/5	5
PXDC1	ENST00000485986.1	n.40G>T		non_coding_transcript_exon_variant	1/3	2
ENSG00000270504	ENST00000603791.1	n.380C>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452092 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721974

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 14, 2024

The c.42G>T (p.M14I) alteration is located in exon 1 (coding exon 1) of the PXDC1 gene. This alteration results from a G to T substitution at nucleotide position 42, causing the methionine (M) at amino acid position 14 to be replaced by an isoleucine (I). 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	0.97
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.85	P
Vest4		0.77
MutPred		0.31		Gain of sheet (P = 0.0125);
MVP		0.36
MPC		1.2
ClinPred		0.90	D
GERP RS		3.5
Varity_R		0.55
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-3751724;