10-103602184-C-T

Variant names:

• chr10-103602184-C-T
• rs75922594
• NM_001394015.1:c.3034G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001394015.1(SH3PXD2A):​c.3034G>A​(p.Val1012Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00108 in 1,575,330 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (10 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: SH3PXD2A NM_001394015.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.87
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00867787).
• BP6: Variant 10-103602184-C-T is Benign according to our data. Variant chr10-103602184-C-T is described in ClinVar as Benign. ClinVar VariationId is 717164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00523 (797/152276) while in subpopulation AFR AF = 0.0179 (745/41564). AF 95% confidence interval is 0.0169. There are 10 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 797 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.3034G>A	p.Val1012Ile	missense	Exon 15 of 15	NP_001380944.1	Q5TCZ1-1
	SH3PXD2A	NM_014631.3		c.2950G>A	p.Val984Ile	missense	Exon 14 of 14	NP_055446.2
	SH3PXD2A	NM_001365079.1		c.2677G>A	p.Val893Ile	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.3034G>A	p.Val1012Ile	missense	Exon 15 of 15	ENSP00000358789.4	Q5TCZ1-1
	SH3PXD2A	ENST00000355946.7	TSL:1	c.2950G>A	p.Val984Ile	missense	Exon 14 of 14	ENSP00000348215.2	Q5TCZ1-3
	SH3PXD2A	ENST00000315994.6	TSL:1	n.2840G>A		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 797 AN: 152158 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00171 AC: 376 AN: 220344 AF XY: 0.00125

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000675

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000630 AC: 897 AN: 1423054 Hom.: 6 Cov.: 62 AF XY: 0.000546 AC XY: 384 AN XY: 702890

African (AFR) AF: 0.0193 AC: 627 AN: 32560

American (AMR) AF: 0.00106 AC: 44 AN: 41528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23342

East Asian (EAS) AF: 0.000458 AC: 18 AN: 39296

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79372

European-Finnish (FIN) AF: 0.0000386 AC: 2 AN: 51832

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5558

European-Non Finnish (NFE) AF: 0.000131 AC: 143 AN: 1090948

Other (OTH) AF: 0.00101 AC: 59 AN: 58618

GnomAD4 genome AF: 0.00523 AC: 797 AN: 152276 Hom.: 10 Cov.: 33 AF XY: 0.00467 AC XY: 348 AN XY: 74450

African (AFR) AF: 0.0179 AC: 745 AN: 41564

American (AMR) AF: 0.00196 AC: 30 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00149 Hom.: 3

Bravo AF: 0.00617

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00190 AC: 230

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.9
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.15
Sift	Benign	0.045	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.25
MVP		0.74
MPC		0.97
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.39
Mutation Taster		=55/45	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: rs75922594; hg19: chr10-105361941;