6-3727577-C-G

Variant names:

• chr6-3727577-C-G
• rs226959
• NM_183373.4:c.552G>C

Variant summary

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

The NM_183373.4(PXDC1):​c.552G>C​(p.Gln184His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.66 in 1,608,920 control chromosomes in the GnomAD database, including 351,580 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (33190 hom., cov: 33)
  • Exomes 𝑓: 0.66 (318390 hom.)
• Consequence: PXDC1 NM_183373.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.975
• Publications: 39 publications found

Genes affected

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.343562E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXDC1	NM_183373.4	c.552G>C	p.Gln184His	missense_variant	Exon 4 of 5	ENST00000380283.5	NP_899229.2
PXDC1	XM_011514393.4	c.369G>C	p.Gln123His	missense_variant	Exon 5 of 6		XP_011512695.1
PXDC1	XM_047418376.1	c.369G>C	p.Gln123His	missense_variant	Exon 4 of 5		XP_047274332.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXDC1	ENST00000380283.5	c.552G>C	p.Gln184His	missense_variant	Exon 4 of 5	1	NM_183373.4	ENSP00000369636.5
PXDC1	ENST00000380277.6	c.393G>C	p.Gln131His	missense_variant	Exon 4 of 5	3		ENSP00000369630.2
PXDC1	ENST00000477592.2	n.548G>C		non_coding_transcript_exon_variant	Exon 4 of 5	5

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100245 AN: 152004 Hom.: 33153 Cov.: 33

Gnomad AFR AF: 0.666

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.662

Gnomad OTH AF: 0.634

GnomAD2 exomes AF: 0.659 AC: 165564 AN: 251230 AF XY: 0.662

Gnomad AFR exome AF: 0.662

Gnomad AMR exome AF: 0.617

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.607

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.663

Gnomad OTH exome AF: 0.663

GnomAD4 exome AF: 0.660 AC: 962092 AN: 1456798 Hom.: 318390 Cov.: 33 AF XY: 0.661 AC XY: 479486 AN XY: 725098

African (AFR) AF: 0.672 AC: 22454 AN: 33390

American (AMR) AF: 0.617 AC: 27573 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 18295 AN: 26102

East Asian (EAS) AF: 0.594 AC: 23552 AN: 39646

South Asian (SAS) AF: 0.678 AC: 58345 AN: 86094

European-Finnish (FIN) AF: 0.698 AC: 37291 AN: 53410

Middle Eastern (MID) AF: 0.659 AC: 3792 AN: 5754

European-Non Finnish (NFE) AF: 0.660 AC: 730772 AN: 1107470

Other (OTH) AF: 0.664 AC: 40018 AN: 60230

GnomAD4 genome AF: 0.660 AC: 100326 AN: 152122 Hom.: 33190 Cov.: 33 AF XY: 0.659 AC XY: 48984 AN XY: 74366

African (AFR) AF: 0.667 AC: 27671 AN: 41506

American (AMR) AF: 0.605 AC: 9253 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2410 AN: 3472

East Asian (EAS) AF: 0.590 AC: 3044 AN: 5158

South Asian (SAS) AF: 0.674 AC: 3253 AN: 4826

European-Finnish (FIN) AF: 0.709 AC: 7501 AN: 10584

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.662 AC: 44964 AN: 67966

Other (OTH) AF: 0.629 AC: 1332 AN: 2116

Alfa AF: 0.669 Hom.: 11069

Bravo AF: 0.654

TwinsUK AF: 0.657 AC: 2437

ALSPAC AF: 0.662 AC: 2551

ESP6500AA AF: 0.655 AC: 2884

ESP6500EA AF: 0.661 AC: 5681

ExAC AF: 0.660 AC: 80115

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0074	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000023	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.97
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.10
Sift	Benign	0.29	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.079		Gain of disorder (P = 0.1614);
MPC		0.38
ClinPred		0.010	T
GERP RS		4.5
Varity_R		0.045
gMVP		0.22
Mutation Taster		=99/1	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: rs226959; hg19: chr6-3727811; COSMIC: COSV66661258;