NM_014474.4:c.61+654A>T

Variant names:

• chr1-27935898-A-T
• rs4409675
• NM_014474.4:c.61+654A>T

Variant summary

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

The NM_014474.4(SMPDL3B):​c.61+654A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 151,764 control chromosomes in the GnomAD database, including 29,239 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 0.61 (29239 hom., cov: 30)
• Consequence: SMPDL3B NM_014474.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 10 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPDL3B	NM_014474.4	c.61+654A>T		intron_variant	Intron 1 of 7	ENST00000373894.8	NP_055289.2
SMPDL3B	NM_001009568.3	c.61+654A>T		intron_variant	Intron 1 of 6		NP_001009568.1
SMPDL3B	NM_001304579.2	c.-629+654A>T		intron_variant	Intron 1 of 7		NP_001291508.1
SMPDL3B	XM_011541259.3	c.61+654A>T		intron_variant	Intron 1 of 8		XP_011539561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPDL3B	ENST00000373894.8	c.61+654A>T		intron_variant	Intron 1 of 7	1	NM_014474.4	ENSP00000363001.3

Frequencies

GnomAD3 genomes AF: 0.607 AC: 91979 AN: 151646 Hom.: 29222 Cov.: 30

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.553

Gnomad AMR AF: 0.648

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.610

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.606 AC: 92025 AN: 151764 Hom.: 29239 Cov.: 30 AF XY: 0.608 AC XY: 45078 AN XY: 74164

African (AFR) AF: 0.411 AC: 16994 AN: 41340

American (AMR) AF: 0.649 AC: 9889 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2369 AN: 3470

East Asian (EAS) AF: 0.403 AC: 2081 AN: 5164

South Asian (SAS) AF: 0.702 AC: 3373 AN: 4808

European-Finnish (FIN) AF: 0.667 AC: 7012 AN: 10506

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48328 AN: 67934

Other (OTH) AF: 0.613 AC: 1288 AN: 2100

Alfa AF: 0.644 Hom.: 3868

Bravo AF: 0.590

Asia WGS AF: 0.617 AC: 2148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.059
DANN	Benign	0.82
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs4409675; hg19: chr1-28262409; COSMIC: COSV65870283; COSMIC: COSV65870283;