6-122789365-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006714.5(SMPDL3A):​c.19C>T​(p.Leu7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,395,146 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SMPDL3A NM_006714.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039587528).

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>T	p.Leu7Phe	missense	Exon 1 of 8	NP_006705.1	Q92484-1
	SMPDL3A	NM_001286138.2		c.-161C>T		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>T	p.Leu7Phe	missense	Exon 1 of 8	ENSP00000357425.4	Q92484-1
	SMPDL3A	ENST00000894537.1		c.19C>T	p.Leu7Phe	missense	Exon 1 of 7	ENSP00000564596.1
	SMPDL3A	ENST00000894534.1		c.19C>T	p.Leu7Phe	missense	Exon 1 of 6	ENSP00000564593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000837 AC: 12 AN: 143314 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1395146 Hom.: 0 Cov.: 30 AF XY: 0.00000727 AC XY: 5 AN XY: 688028

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

American (AMR) AF: 0.000505 AC: 18 AN: 35614

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: 0.00 AC: 0 AN: 1077856

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.6
DANN	Benign	0.89
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.28
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.015
Sift	Benign	0.30	T
Sift4G	Benign	0.13	T
Polyphen		0.0050	B
Vest4		0.052
MutPred		0.40		Loss of helix (P = 0.0626)
MVP		0.085
MPC		0.095
ClinPred		0.022	T
GERP RS		0.54
PromoterAI		0.023	Neutral
Varity_R		0.049
gMVP		0.24
Mutation Taster		=91/9	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;