chr1-27945246-A-G

Position:

• chr1-27945246-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014474.4(SMPDL3B):​c.76A>G​(p.Ile26Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMPDL3B NM_014474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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]

SMPDL3B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23545536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPDL3B	NM_014474.4	c.76A>G	p.Ile26Val	missense_variant	2/8	ENST00000373894.8	NP_055289.2
SMPDL3B	NM_001009568.3	c.76A>G	p.Ile26Val	missense_variant	2/7		NP_001009568.1
SMPDL3B	XM_011541259.3	c.166A>G	p.Ile56Val	missense_variant	3/9		XP_011539561.1
SMPDL3B	NM_001304579.2	c.-614A>G		5_prime_UTR_variant	2/8		NP_001291508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPDL3B	ENST00000373894.8	c.76A>G	p.Ile26Val	missense_variant	2/8	1	NM_014474.4	ENSP00000363001.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.76A>G (p.I26V) alteration is located in exon 2 (coding exon 2) of the SMPDL3B gene. This alteration results from a A to G substitution at nucleotide position 76, causing the isoleucine (I) at amino acid position 26 to be replaced by a valine (V). 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	0.087
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.19	T;T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.38	N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.87	T;T;T;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.67	P;.;B;P
Vest4		0.23
MutPred		0.56		Loss of catalytic residue at L31 (P = 0.0195);.;Loss of catalytic residue at L31 (P = 0.0195);Loss of catalytic residue at L31 (P = 0.0195);
MVP		0.70
MPC		0.25
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.047
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1052018019; hg19: chr1-28271757;