20-62957563-T-C

Variant names:

• chr20-62957563-T-C
• rs746426893
• NM_022082.4:c.380T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022082.4(SLC17A9):​c.380T>C​(p.Leu127Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC17A9 NM_022082.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC17A9	NM_022082.4	c.380T>C	p.Leu127Pro	missense_variant	Exon 3 of 13	ENST00000370351.9	NP_071365.4
SLC17A9	NM_001302643.2	c.362T>C	p.Leu121Pro	missense_variant	Exon 4 of 14		NP_001289572.2
SLC17A9	XM_011528978.3	c.20T>C	p.Leu7Pro	missense_variant	Exon 2 of 12		XP_011527280.1
SLC17A9	XR_936601.4	n.502T>C		non_coding_transcript_exon_variant	Exon 3 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC17A9	ENST00000370351.9	c.380T>C	p.Leu127Pro	missense_variant	Exon 3 of 13	1	NM_022082.4	ENSP00000359376.4
SLC17A9	ENST00000370349.7	c.362T>C	p.Leu121Pro	missense_variant	Exon 4 of 14	1		ENSP00000359374.3
SLC17A9	ENST00000411611.1	c.440T>C	p.Leu147Pro	missense_variant	Exon 3 of 3	2		ENSP00000388215.1
SLC17A9	ENST00000488738.5	n.500T>C		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1421658 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 705378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380T>C (p.L127P) alteration is located in exon 3 (coding exon 3) of the SLC17A9 gene. This alteration results from a T to C substitution at nucleotide position 380, causing the leucine (L) at amino acid position 127 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.87		Loss of stability (P = 0.025);.;.;
MVP		0.53
MPC		1.7
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs746426893; hg19: chr20-61588915;