17-4499168-G-A

Variant names:

• chr17-4499168-G-A
• rs1453027012
• NM_001124758.3:c.121G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001124758.3(SPNS2):​c.121G>A​(p.Gly41Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 1,224,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G41W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

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]

SPNS2-AS1 (HGNC:55787): (SPNS2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2314848).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001124758.3. 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
	SPNS2	NM_001124758.3	MANE Select	c.121G>A	p.Gly41Arg	missense	Exon 1 of 13	NP_001118230.1	Q8IVW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPNS2	ENST00000329078.8	TSL:1 MANE Select	c.121G>A	p.Gly41Arg	missense	Exon 1 of 13	ENSP00000333292.3	Q8IVW8
	SPNS2	ENST00000947403.1		c.121G>A	p.Gly41Arg	missense	Exon 1 of 13	ENSP00000617462.1
	SPNS2	ENST00000932033.1		c.121G>A	p.Gly41Arg	missense	Exon 1 of 12	ENSP00000602092.1

Frequencies

GnomAD3 genomes AF: 0.00000667 AC: 1 AN: 149884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1310 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ 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: 0.00000186 AC: 2 AN: 1075110 Hom.: 0 Cov.: 30 AF XY: 0.00000195 AC XY: 1 AN XY: 512542

African (AFR) AF: 0.00 AC: 0 AN: 22110

American (AMR) AF: 0.00 AC: 0 AN: 7834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13330

East Asian (EAS) AF: 0.00 AC: 0 AN: 24588

South Asian (SAS) AF: 0.00 AC: 0 AN: 23374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2834

European-Non Finnish (NFE) AF: 0.00000218 AC: 2 AN: 917408

Other (OTH) AF: 0.00 AC: 0 AN: 42348

GnomAD4 genome AF: 0.00000667 AC: 1 AN: 149884 Hom.: 0 Cov.: 32 AF XY: 0.0000137 AC XY: 1 AN XY: 73100

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

African (AFR) AF: 0.00 AC: 0 AN: 41162

American (AMR) AF: 0.00 AC: 0 AN: 15074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67104

Other (OTH) AF: 0.00 AC: 0 AN: 2056

⚠️ 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: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.20
MutPred		0.34		Gain of methylation at G41 (P = 0.0056)
MVP		0.23
MPC		0.95
ClinPred		0.41	T
GERP RS		3.1
PromoterAI		0.0039	Neutral
Varity_R		0.14
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1453027012; hg19: chr17-4402463;