NM_006714.5:c.19C>G

Variant names:

• chr6-122789365-C-G
• rs1329225568
• NM_006714.5:c.19C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006714.5(SMPDL3A):​c.19C>G​(p.Leu7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. L7F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SMPDL3A NM_006714.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• Publications: 0 publications found

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]

SMPDL3A Gene-Disease associations (from GenCC):

• sensory peripheral neuropathy

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000294893 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0678398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006714.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPDL3A	NM_006714.5	MANE Select	c.19C>G	p.Leu7Val	missense	Exon 1 of 8	NP_006705.1	Q92484-1
	SMPDL3A	NM_001286138.2		c.-161C>G		5_prime_UTR	Exon 1 of 7	NP_001273067.1	Q92484-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPDL3A	ENST00000368440.5	TSL:1 MANE Select	c.19C>G	p.Leu7Val	missense	Exon 1 of 8	ENSP00000357425.4	Q92484-1
	SMPDL3A	ENST00000894537.1		c.19C>G	p.Leu7Val	missense	Exon 1 of 7	ENSP00000564596.1
	SMPDL3A	ENST00000894534.1		c.19C>G	p.Leu7Val	missense	Exon 1 of 6	ENSP00000564593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1395148 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688030

African (AFR) AF: 0.00 AC: 0 AN: 31442

American (AMR) AF: 0.00 AC: 0 AN: 35616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25086

East Asian (EAS) AF: 0.00 AC: 0 AN: 35672

South Asian (SAS) AF: 0.00 AC: 0 AN: 79050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077856

Other (OTH) AF: 0.00 AC: 0 AN: 57856

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.3
DANN	Benign	0.94
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.28
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.0060
Sift	Benign	0.037	D
Sift4G	Uncertain	0.023	D
Polyphen		0.23	B
Vest4		0.058
MutPred		0.37		Loss of helix (P = 0.0626)
MVP		0.20
MPC		0.088
ClinPred		0.18	T
GERP RS		0.54
PromoterAI		0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.057
gMVP		0.26
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1329225568; hg19: chr6-123110510;