NM_024083.4:c.326G>T

Variant names:

• chr17-81985559-G-T
• rs986220755
• NM_024083.4:c.326G>T

Variant summary

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

The NM_024083.4(ASPSCR1):​c.326G>T​(p.Cys109Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ASPSCR1 NM_024083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.211
• Publications: 0 publications found

Genes affected

ASPSCR1 (HGNC:13825): (ASPSCR1 tether for SLC2A4, UBX domain containing) The protein encoded by this gene contains a UBX domain and interacts with glucose transporter type 4 (GLUT4). This protein is a tether, which sequesters the GLUT4 in intracellular vesicles in muscle and fat cells in the absence of insulin, and redistributes the GLUT4 to the plasma membrane within minutes of insulin stimulation. Translocation t(X;17)(p11;q25) of this gene with transcription factor TFE3 gene results in a ASPSCR1-TFE3 fusion protein in alveolar soft part sarcoma and in renal cell carcinomas. Multiple alternatively spliced transcript variants have been found. [provided by RefSeq, Oct 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.11458942).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024083.4. 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
	ASPSCR1	NM_024083.4	MANE Select	c.326G>T	p.Cys109Phe	missense	Exon 4 of 16	NP_076988.1	Q9BZE9-1
	ASPSCR1	NM_001251888.2		c.326G>T	p.Cys109Phe	missense	Exon 4 of 17	NP_001238817.1	Q9BZE9-2
	ASPSCR1	NM_001330528.2		c.95G>T	p.Cys32Phe	missense	Exon 3 of 15	NP_001317457.1	Q9BZE9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPSCR1	ENST00000306739.9	TSL:1 MANE Select	c.326G>T	p.Cys109Phe	missense	Exon 4 of 16	ENSP00000302176.4	Q9BZE9-1
	ASPSCR1	ENST00000584454.5	TSL:1	n.95G>T		non_coding_transcript_exon	Exon 4 of 17	ENSP00000463992.1	J3QR12
	ASPSCR1	ENST00000306729.11	TSL:2	c.326G>T	p.Cys109Phe	missense	Exon 4 of 17	ENSP00000306625.7	Q9BZE9-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152274 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00000796 AC: 2 AN: 251106 AF XY: 0.00000736

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727120

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74398

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.21
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.14
Sift	Benign	0.36	T
Sift4G	Uncertain	0.037	D
Polyphen		0.0020	B
Vest4		0.21
MutPred		0.27		Gain of disorder (P = 0.1906)
MVP		0.29
MPC		0.17
ClinPred		0.094	T
GERP RS		2.0
Varity_R		0.15
gMVP		0.35
Mutation Taster		=87/13	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: rs986220755; hg19: chr17-79943435; COSMIC: COSV100144645; COSMIC: COSV100144645;