chr1-27953302-T-C

Position:

• chr1-27953302-T-C

Variant summary

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

The NM_014474.4(SMPDL3B):​c.461T>C​(p.Ile154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,613,812 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I154R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SMPDL3B NM_014474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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]

ENSG00000227050 (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=0.17775282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPDL3B	NM_014474.4	c.461T>C	p.Ile154Thr	missense_variant	4/8	ENST00000373894.8	NP_055289.2
SMPDL3B	NM_001009568.3	c.461T>C	p.Ile154Thr	missense_variant	4/7		NP_001009568.1
SMPDL3B	XM_011541259.3	c.551T>C	p.Ile184Thr	missense_variant	5/9		XP_011539561.1
SMPDL3B	NM_001304579.2	c.-158T>C		5_prime_UTR_variant	4/8		NP_001291508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPDL3B	ENST00000373894.8	c.461T>C	p.Ile154Thr	missense_variant	4/8	1	NM_014474.4	ENSP00000363001.3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251356 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135862

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000896 AC: 131 AN: 1461634 Hom.: 0 Cov.: 30 AF XY: 0.0000756 AC XY: 55 AN XY: 727116

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74350

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

Aug 29, 2024

The c.461T>C (p.I154T) alteration is located in exon 4 (coding exon 4) of the SMPDL3B gene. This alteration results from a T to C substitution at nucleotide position 461, causing the isoleucine (I) at amino acid position 154 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	9.6
DANN	Benign	0.87
DEOGEN2	Benign	0.23	T;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.61	N;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.028	B;.;B
Vest4		0.31
MVP		0.78
MPC		0.33
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.042
gMVP		0.68

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: rs148814012; hg19: chr1-28279813;