14-63686211-T-C

Variant names:

• chr14-63686211-T-C
• rs1884969928
• NM_030791.4:c.1220A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030791.4(SGPP1):​c.1220A>G​(p.Gln407Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SGPP1 NM_030791.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

SGPP1 (HGNC:17720): (sphingosine-1-phosphate phosphatase 1) Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that regulates diverse biologic processes. SGPP1 catalyzes the degradation of S1P via salvage and recycling of sphingosine into long-chain ceramides (Mandala et al., 2000 [PubMed 10859351]; Le Stunff et al., 2007 [PubMed 17895250]).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGPP1	NM_030791.4	c.1220A>G	p.Gln407Arg	missense_variant	Exon 3 of 3	ENST00000247225.7	NP_110418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGPP1	ENST00000247225.7	c.1220A>G	p.Gln407Arg	missense_variant	Exon 3 of 3	1	NM_030791.4	ENSP00000247225.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1220A>G (p.Q407R) alteration is located in exon 3 (coding exon 3) of the SGPP1 gene. This alteration results from a A to G substitution at nucleotide position 1220, causing the glutamine (Q) at amino acid position 407 to be replaced by an arginine (R). 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	Benign	0.18
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.46
Sift	Benign	0.39	T
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.41		Gain of catalytic residue at E412 (P = 0.0111);
MVP		0.43
MPC		0.62
ClinPred		0.82	D
GERP RS		6.1
Varity_R		0.15
gMVP		0.68

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: rs1884969928; hg19: chr14-64152929;