chr6-122801319-C-T

Variant names:

• chr6-122801319-C-T
• rs28385609
• NM_006714.5:c.481C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006714.5(SMPDL3A):​c.481C>T​(p.Pro161Ser) variant causes a missense change. The variant allele was found at a frequency of 0.136 in 1,606,826 control chromosomes in the GnomAD database, including 16,747 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1158 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15589 hom.)
• Consequence: SMPDL3A NM_006714.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.57
• Publications: 26 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]

ENSG00000294893 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019767582).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

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.481C>T	p.Pro161Ser	missense	Exon 4 of 8	NP_006705.1	Q92484-1
	SMPDL3A	NM_001286138.2		c.88C>T	p.Pro30Ser	missense	Exon 3 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.481C>T	p.Pro161Ser	missense	Exon 4 of 8	ENSP00000357425.4	Q92484-1
	SMPDL3A	ENST00000894535.1		c.481C>T	p.Pro161Ser	missense	Exon 4 of 6	ENSP00000564594.1
	SMPDL3A	ENST00000539041.5	TSL:2	c.88C>T	p.Pro30Ser	missense	Exon 3 of 7	ENSP00000442152.1	Q92484-2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17097 AN: 152118 Hom.: 1161 Cov.: 33

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0847

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.132 AC: 33065 AN: 251040 AF XY: 0.141

Gnomad AFR exome AF: 0.0457

Gnomad AMR exome AF: 0.0606

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.0158

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.139 AC: 201814 AN: 1454590 Hom.: 15589 Cov.: 29 AF XY: 0.142 AC XY: 102915 AN XY: 723952

African (AFR) AF: 0.0488 AC: 1629 AN: 33412

American (AMR) AF: 0.0640 AC: 2857 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 4510 AN: 26066

East Asian (EAS) AF: 0.0172 AC: 681 AN: 39684

South Asian (SAS) AF: 0.228 AC: 19571 AN: 85896

European-Finnish (FIN) AF: 0.178 AC: 9482 AN: 53408

Middle Eastern (MID) AF: 0.183 AC: 1050 AN: 5744

European-Non Finnish (NFE) AF: 0.139 AC: 153926 AN: 1105582

Other (OTH) AF: 0.135 AC: 8108 AN: 60128

GnomAD4 genome AF: 0.112 AC: 17099 AN: 152236 Hom.: 1158 Cov.: 33 AF XY: 0.114 AC XY: 8518 AN XY: 74414

African (AFR) AF: 0.0467 AC: 1939 AN: 41558

American (AMR) AF: 0.0845 AC: 1293 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5180

South Asian (SAS) AF: 0.222 AC: 1072 AN: 4818

European-Finnish (FIN) AF: 0.182 AC: 1930 AN: 10586

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9703 AN: 68012

Other (OTH) AF: 0.114 AC: 240 AN: 2114

Alfa AF: 0.130 Hom.: 4868

Bravo AF: 0.0991

TwinsUK AF: 0.144 AC: 534

ALSPAC AF: 0.140 AC: 538

ESP6500AA AF: 0.0461 AC: 203

ESP6500EA AF: 0.146 AC: 1253

ExAC AF: 0.135 AC: 16382

Asia WGS AF: 0.115 AC: 401 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.142

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0020	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.44
MPC		0.48
ClinPred		0.038	T
GERP RS		5.7
Varity_R		0.89
gMVP		0.86
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs28385609; hg19: chr6-123122464; COSMIC: COSV63755382; COSMIC: COSV63755382;