17-4531050-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001124758.3(SPNS2):c.726-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,613,880 control chromosomes in the GnomAD database, including 541 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (29 hom., cov: 33)
  • Exomes 𝑓: 0.026 (512 hom.)
• Consequence: SPNS2 NM_001124758.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7834
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76

Genes affected

SPNS2 (HGNC:26992): (SPNS lysolipid transporter 2, sphingosine-1-phosphate) The protein encoded by this gene is a transporter of sphingosine 1-phosphate, a secreted lipid that is important in cardiovascular, immunological, and neural development. Defects in this gene are a cause of early onset progressive hearing loss. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 17-4531050-C-T is Benign according to our data. Variant chr17-4531050-C-T is described in ClinVar as [Benign]. Clinvar id is 3037940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0192 (2922/152340) while in subpopulation NFE AF= 0.0276 (1880/68032). AF 95% confidence interval is 0.0266. There are 29 homozygotes in gnomad4. There are 1395 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPNS2	NM_001124758.3	c.726-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000329078.8
SPNS2	XM_047435339.1	c.273-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SPNS2	XR_007065260.1	n.893-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant
SPNS2	XR_007065261.1	n.563-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPNS2	ENST00000329078.8	c.726-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001124758.3	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2922 AN: 152222 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0167

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0292

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0276

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0202 AC: 5007 AN: 248306 Hom.: 69 AF XY: 0.0208 AC XY: 2806 AN XY: 135004

Gnomad AFR exome AF: 0.00383

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00817

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0256 AC: 37398 AN: 1461540 Hom.: 512 Cov.: 32 AF XY: 0.0254 AC XY: 18455 AN XY: 727072

Gnomad4 AFR exome AF: 0.00421

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0377

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00929

Gnomad4 FIN exome AF: 0.0266

Gnomad4 NFE exome AF: 0.0287

Gnomad4 OTH exome AF: 0.0237

GnomAD4 genome AF: 0.0192 AC: 2922 AN: 152340 Hom.: 29 Cov.: 33 AF XY: 0.0187 AC XY: 1395 AN XY: 74482

Gnomad4 AFR AF: 0.00467

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.0292

Gnomad4 NFE AF: 0.0276

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0262 Hom.: 29

Bravo AF: 0.0183

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0317

EpiControl AF: 0.0313

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SPNS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
Cadd	Benign	18
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Benign	0.34
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: rs72830093; hg19: chr17-4434345;