chr10-20046875-A-G

Variant names:

• chr10-20046875-A-G
• rs749590025
• NM_032812.9:c.331A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032812.9(PLXDC2):​c.331A>G​(p.Thr111Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,608,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PLXDC2 NM_032812.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• Publications: 0 publications found

Genes affected

PLXDC2 (HGNC:21013): (plexin domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14096132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXDC2	NM_032812.9	c.331A>G	p.Thr111Ala	missense_variant	Exon 3 of 14	ENST00000377252.5	NP_116201.7
PLXDC2	XM_011519750.3	c.331A>G	p.Thr111Ala	missense_variant	Exon 3 of 14		XP_011518052.1
PLXDC2	NM_001282736.2	c.325-21295A>G		intron_variant	Intron 2 of 12		NP_001269665.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXDC2	ENST00000377252.5	c.331A>G	p.Thr111Ala	missense_variant	Exon 3 of 14	1	NM_032812.9	ENSP00000366460.3
PLXDC2	ENST00000377242.7	c.325-21295A>G		intron_variant	Intron 2 of 12	1		ENSP00000366450.3
PLXDC2	ENST00000377238.2	n.106A>G		non_coding_transcript_exon_variant	Exon 2 of 13	5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000729 AC: 18 AN: 246994 AF XY: 0.0000524

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000479

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1456360 Hom.: 0 Cov.: 30 AF XY: 0.0000152 AC XY: 11 AN XY: 724538

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.000390 AC: 17 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 85226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109790

Other (OTH) AF: 0.0000832 AC: 5 AN: 60122

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.000525 AC: 8 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331A>G (p.T111A) alteration is located in exon 3 (coding exon 3) of the PLXDC2 gene. This alteration results from a A to G substitution at nucleotide position 331, causing the threonine (T) at amino acid position 111 to be replaced by an alanine (A). 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	0.088
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.046
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.28	B
Vest4		0.59
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0098);
MVP		0.082
MPC		0.13
ClinPred		0.12	T
GERP RS		5.3
Varity_R		0.088
gMVP		0.61
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs749590025; hg19: chr10-20335804;