1-27945306-C-T

Position:

• chr1-27945306-C-T

Variant summary

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

The NM_014474.4(SMPDL3B):​c.136C>T​(p.Pro46Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SMPDL3B NM_014474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMPDL3B	NM_014474.4	c.136C>T	p.Pro46Ser	missense_variant	2/8	ENST00000373894.8
SMPDL3B	NM_001009568.3	c.136C>T	p.Pro46Ser	missense_variant	2/7
SMPDL3B	XM_011541259.3	c.226C>T	p.Pro76Ser	missense_variant	3/9
SMPDL3B	NM_001304579.2	c.-554C>T		5_prime_UTR_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMPDL3B	ENST00000373894.8	c.136C>T	p.Pro46Ser	missense_variant	2/8	1	NM_014474.4	P1
	ENST00000448015.1	n.287-6227G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

Dec 21, 2022

The c.136C>T (p.P46S) alteration is located in exon 2 (coding exon 2) of the SMPDL3B gene. This alteration results from a C to T substitution at nucleotide position 136, causing the proline (P) at amino acid position 46 to be replaced by a serine (S). 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	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.50	T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.8	L;.;L;.
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;D;D;N
REVEL	Uncertain	0.49
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.88	T;T;T;T
Polyphen		0.97	D;.;D;D
Vest4		0.38
MutPred		0.57		Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.92
MPC		0.86
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.35
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28271817;