10-103602055-C-T

Variant names:

• chr10-103602055-C-T
• rs375554787
• NM_001394015.1:c.3163G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001394015.1(SH3PXD2A):​c.3163G>A​(p.Val1055Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,607,554 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1055L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000034 (1 hom.)
• Consequence: SH3PXD2A NM_001394015.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028925389).
• BS2: High AC in GnomAdExome4 at 49 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2A	NM_001394015.1	MANE Select	c.3163G>A	p.Val1055Met	missense	Exon 15 of 15	NP_001380944.1	Q5TCZ1-1
	SH3PXD2A	NM_014631.3		c.3079G>A	p.Val1027Met	missense	Exon 14 of 14	NP_055446.2
	SH3PXD2A	NM_001365079.1		c.2806G>A	p.Val936Met	missense	Exon 9 of 9	NP_001352008.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3PXD2A	ENST00000369774.9	TSL:5 MANE Select	c.3163G>A	p.Val1055Met	missense	Exon 15 of 15	ENSP00000358789.4	Q5TCZ1-1
	SH3PXD2A	ENST00000355946.7	TSL:1	c.3079G>A	p.Val1027Met	missense	Exon 14 of 14	ENSP00000348215.2	Q5TCZ1-3
	SH3PXD2A	ENST00000315994.6	TSL:1	n.2969G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000965

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000530 AC: 13 AN: 245398 AF XY: 0.0000680

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000382

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000337 AC: 49 AN: 1455288 Hom.: 1 Cov.: 32 AF XY: 0.0000373 AC XY: 27 AN XY: 723166

African (AFR) AF: 0.000120 AC: 4 AN: 33380

American (AMR) AF: 0.0000226 AC: 1 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.0000389 AC: 1 AN: 25674

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39650

South Asian (SAS) AF: 0.0000235 AC: 2 AN: 85198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1108064

Other (OTH) AF: 0.0000832 AC: 5 AN: 60068

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152266 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74454

African (AFR) AF: 0.0000963 AC: 4 AN: 41558

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000454 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

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	0.23
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.058
Sift	Benign	0.037	D
Sift4G	Benign	0.11	T
Polyphen		0.16	B
Vest4		0.13
MVP		0.30
MPC		0.36
ClinPred		0.039	T
GERP RS		3.4
Varity_R		0.056
gMVP		0.31
Mutation Taster		=92/8	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: rs375554787; hg19: chr10-105361812; COSMIC: COSV60119752;