Genetic Variant SH3PXD2A:p.Asn1127Thr (chr10-103601838-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001394015.1(SH3PXD2A):c.3380A>C(p.Asn1127Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,607,744 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: 𝑓 0.0000066 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SH3PXD2A
NM_001394015.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

Genes affected

SH3PXD2A (HGNC:23664): (SH3 and PX domains 2A) Predicted to enable superoxide-generating NADPH oxidase activator activity. Involved in osteoclast fusion and superoxide metabolic process. Located in podosome. [provided by Alliance of Genome Resources, Apr 2022]

SH3PXD2A links:

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ACMG classification

Classification was made for transcript

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

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394015.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3PXD2A	NM_001394015.1	MANE Select	c.3380A>C	p.Asn1127Thr	missense	Exon 15 of 15	NP_001380944.1	Q5TCZ1-1
SH3PXD2A	NM_014631.3		c.3296A>C	p.Asn1099Thr	missense	Exon 14 of 14	NP_055446.2
SH3PXD2A	NM_001365079.1		c.3023A>C	p.Asn1008Thr	missense	Exon 9 of 9	NP_001352008.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3PXD2A	ENST00000369774.9	TSL:5 MANE Select	c.3380A>C	p.Asn1127Thr	missense	Exon 15 of 15	ENSP00000358789.4	Q5TCZ1-1
SH3PXD2A	ENST00000355946.7	TSL:1	c.3296A>C	p.Asn1099Thr	missense	Exon 14 of 14	ENSP00000348215.2	Q5TCZ1-3
SH3PXD2A	ENST00000315994.6	TSL:1	n.3186A>C		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456112

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33282

American (AMR)

AF:

0.00

AC:

AN:

44096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25640

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

85500

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000361

AC:

AN:

1108864

Other (OTH)

AF:

0.00

AC:

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41292

American (AMR)

AF:

0.00

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5124

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67934

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.020

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.56

MutationAssessor

Benign

1.7

PhyloP100

8.0

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.37

Sift

Benign

0.29

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.81

MutPred

0.84

Loss of ubiquitination at K1132 (P = 0.063)

MVP

0.57

MPC

1.1

ClinPred

0.99

GERP RS

5.4

Varity_R

0.58

gMVP

0.92

Mutation Taster

=3/97

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over