chr20-62956963-G-T

Position:

• chr20-62956963-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 5P and 12B. PVS1_Strong PP3 BP6_Very_Strong BS2

The ENST00000370351.9(SLC17A9):​c.257+1G>T variant causes a splice donor 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 ENST00000370351.9 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.90

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15026698 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]
• 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/exons	MANE	Protein	UniProt
SLC17A9	NM_022082.4	c.257+1G>T		splice_donor_variant		ENST00000370351.9	NP_071365.4
SLC17A9	NM_001302643.2	c.239+1G>T		splice_donor_variant			NP_001289572.2
SLC17A9	XM_011528978.3	c.-104+27G>T		intron_variant			XP_011527280.1
SLC17A9	XR_936601.4	n.379+1G>T		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC17A9	ENST00000370351.9	c.257+1G>T		splice_donor_variant		1	NM_022082.4	ENSP00000359376	P1
SLC17A9	ENST00000370349.7	c.239+1G>T		splice_donor_variant		1		ENSP00000359374
SLC17A9	ENST00000411611.1	c.317+1G>T		splice_donor_variant		2		ENSP00000388215
SLC17A9	ENST00000488738.5	n.377+1G>T		splice_donor_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.000915 AC: 226 AN: 246882 Hom.: 2 AF XY: 0.000565 AC XY: 76 AN XY: 134524

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.000944

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

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00237

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

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
MutationTaster	Benign	1.0	D;D
GERP RS		4.8

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

Publications

LitVar

Other links and lift over

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