1-27954359-T-A

Position:

• chr1-27954359-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014474.4(SMPDL3B):​c.523T>A​(p.Phe175Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,436 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SMPDL3B NM_014474.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18

Genes affected

SMPDL3B (HGNC:21416): (sphingomyelin phosphodiesterase acid like 3B) Enables phosphoric diester hydrolase activity. Predicted to be involved in membrane lipid catabolic process; negative regulation of inflammatory response; and negative regulation of toll-like receptor signaling pathway. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPDL3B	NM_014474.4	c.523T>A	p.Phe175Ile	missense_variant	5/8	ENST00000373894.8
SMPDL3B	NM_001009568.3	c.523T>A	p.Phe175Ile	missense_variant	5/7
SMPDL3B	XM_011541259.3	c.613T>A	p.Phe205Ile	missense_variant	6/9
SMPDL3B	NM_001304579.2	c.-96T>A		5_prime_UTR_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPDL3B	ENST00000373894.8	c.523T>A	p.Phe175Ile	missense_variant	5/8	1	NM_014474.4	P1
	ENST00000448015.1	n.286+1412A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250516 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461436 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726992

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: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;D;.;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.72
MutPred		0.68		Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;
MVP		0.96
MPC		0.98
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.79
gMVP		0.92

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: rs371222599; hg19: chr1-28280870;