NM_022082.4:c.257+1G>T

Variant names:

• chr20-62956963-G-T
• rs200943155
• NM_022082.4:c.257+1G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS2

The NM_022082.4(SLC17A9):​c.257+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,613,266 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (3 hom.)
• Consequence: SLC17A9 NM_022082.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.90
• Publications: 0 publications found

Genes affected

SLC17A9 (HGNC:16192): (solute carrier family 17 member 9) This gene encodes a member of a family of transmembrane proteins that are involved in the transport of small molecules. The encoded protein participates in the vesicular uptake, storage, and secretion of adenoside triphosphate (ATP) and other nucleotides. A mutation in this gene was found in individuals with autosomal dominant disseminated superficial actinic porokeratosis-8. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

SLC17A9 Gene-Disease associations (from GenCC):

• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• porokeratosis 8, disseminated superficial actinic type

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15102975 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.4, offset of 31, new splice context is: ctgGTgggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 20-62956963-G-T is Benign according to our data. Variant chr20-62956963-G-T is described in ClinVar as [Benign]. Clinvar id is 709518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 595 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A9	NM_022082.4	c.257+1G>T		splice_donor_variant, intron_variant	Intron 2 of 12	ENST00000370351.9	NP_071365.4
SLC17A9	NM_001302643.2	c.239+1G>T		splice_donor_variant, intron_variant	Intron 3 of 13		NP_001289572.2
SLC17A9	XM_011528978.3	c.-104+27G>T		intron_variant	Intron 1 of 11		XP_011527280.1
SLC17A9	XR_936601.4	n.379+1G>T		splice_donor_variant, intron_variant	Intron 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A9	ENST00000370351.9	c.257+1G>T		splice_donor_variant, intron_variant	Intron 2 of 12	1	NM_022082.4	ENSP00000359376.4
SLC17A9	ENST00000370349.7	c.239+1G>T		splice_donor_variant, intron_variant	Intron 3 of 13	1		ENSP00000359374.3
SLC17A9	ENST00000411611.1	c.317+1G>T		splice_donor_variant, intron_variant	Intron 2 of 2	2		ENSP00000388215.1
SLC17A9	ENST00000488738.5	n.377+1G>T		splice_donor_variant, intron_variant	Intron 2 of 10	2

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 596 AN: 152222 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

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: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000915 AC: 226 AN: 246882 AF XY: 0.000565

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000832

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1460926 Hom.: 3 Cov.: 78 AF XY: 0.000327 AC XY: 238 AN XY: 726794

African (AFR) AF: 0.0139 AC: 465 AN: 33478

American (AMR) AF: 0.000939 AC: 42 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52546

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111958

Other (OTH) AF: 0.000944 AC: 57 AN: 60376

GnomAD4 genome AF: 0.00391 AC: 595 AN: 152340 Hom.: 1 Cov.: 34 AF XY: 0.00368 AC XY: 274 AN XY: 74498

African (AFR) AF: 0.0130 AC: 542 AN: 41572

American (AMR) AF: 0.00287 AC: 44 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000905 Hom.: 0

Bravo AF: 0.00451

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0046	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		8.9
GERP RS		4.8
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200943155; hg19: chr20-61588315; COSMIC: COSV99059296;