NM_001124758.3:c.53A>C

Variant names:

• chr17-4499100-A-C
• rs1043497693
• NM_001124758.3:c.53A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001124758.3(SPNS2):​c.53A>C​(p.Glu18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,072,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SPNS2 NM_001124758.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11736703).

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.53A>C	p.Glu18Ala	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.53A>C	p.Glu18Ala	missense	Exon 1 of 13	ENSP00000333292.3	Q8IVW8
	SPNS2	ENST00000947403.1		c.53A>C	p.Glu18Ala	missense	Exon 1 of 13	ENSP00000617462.1
	SPNS2	ENST00000932033.1		c.53A>C	p.Glu18Ala	missense	Exon 1 of 12	ENSP00000602092.1

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 21 AN: 146224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000338

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: 0.000167

Gnomad OTH AF: 0.000493

GnomAD4 exome AF: 0.000128 AC: 119 AN: 926116 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 51 AN XY: 434880

African (AFR) AF: 0.0000555 AC: 1 AN: 18002

American (AMR) AF: 0.00 AC: 0 AN: 3968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8102

East Asian (EAS) AF: 0.00 AC: 0 AN: 10092

South Asian (SAS) AF: 0.0000553 AC: 1 AN: 18078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2122

European-Non Finnish (NFE) AF: 0.000142 AC: 117 AN: 822000

Other (OTH) AF: 0.00 AC: 0 AN: 33116

GnomAD4 genome AF: 0.000144 AC: 21 AN: 146224 Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 12 AN XY: 71188

African (AFR) AF: 0.0000991 AC: 4 AN: 40358

American (AMR) AF: 0.000338 AC: 5 AN: 14796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3378

East Asian (EAS) AF: 0.00 AC: 0 AN: 4938

South Asian (SAS) AF: 0.00 AC: 0 AN: 4676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.000167 AC: 11 AN: 65956

Other (OTH) AF: 0.000493 AC: 1 AN: 2028

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000121

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	23
DANN	Benign	0.86
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.50	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.84
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.046
Sift	Benign	0.043	D
Sift4G	Benign	0.67	T
Polyphen		0.092	B
Vest4		0.18
MutPred		0.16		Gain of helix (P = 0.0199)
MVP		0.40
MPC		0.85
ClinPred		0.18	T
GERP RS		3.5
PromoterAI		-0.065	Neutral
Varity_R		0.092
Mutation Taster		=86/14	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: rs1043497693; hg19: chr17-4402395;