6-122801376-G-A

Position:

• chr6-122801376-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006714.5(SMPDL3A):​c.538G>A​(p.Asp180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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: 33)
• Consequence: SMPDL3A NM_006714.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

Genes affected

SMPDL3A (HGNC:17389): (sphingomyelin phosphodiesterase acid like 3A) Enables phosphoric diester hydrolase activity and zinc ion binding activity. Involved in nucleoside triphosphate catabolic process. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067202896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPDL3A	NM_006714.5	c.538G>A	p.Asp180Asn	missense_variant	4/8	ENST00000368440.5	NP_006705.1
SMPDL3A	NM_001286138.2	c.145G>A	p.Asp49Asn	missense_variant	3/7		NP_001273067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPDL3A	ENST00000368440.5	c.538G>A	p.Asp180Asn	missense_variant	4/8	1	NM_006714.5	ENSP00000357425.4
SMPDL3A	ENST00000539041.5	c.145G>A	p.Asp49Asn	missense_variant	3/7	2		ENSP00000442152.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

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

Oct 20, 2024

The c.538G>A (p.D180N) alteration is located in exon 4 (coding exon 4) of the SMPDL3A gene. This alteration results from a G to A substitution at nucleotide position 538, causing the aspartic acid (D) at amino acid position 180 to be replaced by an asparagine (N). 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	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.80
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.090	.;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.69	N;N
REVEL	Benign	0.098
Sift	Benign	0.53	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0020	.;B
Vest4		0.11
MutPred		0.50		.;Gain of ubiquitination at K176 (P = 0.0898);
MVP		0.70
MPC		0.086
ClinPred		0.23	T
GERP RS		1.0
Varity_R		0.34
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-123122521;