rs114874902

Variant names:

• chr11-6390467-G-A
• rs114874902
• ENST00000533196.1:n.28G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000533196.1(SMPD1):​n.28G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,485,414 control chromosomes in the GnomAD database, including 16 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 0.0057 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (8 hom.)
• Consequence: SMPD1 ENST00000533196.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.227
• Publications: 0 publications found

Genes affected

SMPD1 (HGNC:11120): (sphingomyelin phosphodiesterase 1) The protein encoded by this gene is a lysosomal acid sphingomyelinase that converts sphingomyelin to ceramide. The encoded protein also has phospholipase C activity. Defects in this gene are a cause of Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB). Multiple transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

SMPD1 Gene-Disease associations (from GenCC):

• acid sphingomyelinase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Niemann-Pick disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Niemann-Pick disease type A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• Niemann-Pick disease type B

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000308330 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00573 (873/152260) while in subpopulation AFR AF = 0.019 (789/41558). AF 95% confidence interval is 0.0179. There are 8 homozygotes in GnomAd4. There are 389 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.-132G>A		upstream_gene_variant		ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.-132G>A		upstream_gene_variant		1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152142 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000748 AC: 997 AN: 1333154 Hom.: 8 Cov.: 26 AF XY: 0.000683 AC XY: 448 AN XY: 655764

African (AFR) AF: 0.0185 AC: 556 AN: 30124

American (AMR) AF: 0.00131 AC: 41 AN: 31392

Ashkenazi Jewish (ASJ) AF: 0.00675 AC: 158 AN: 23406

East Asian (EAS) AF: 0.00 AC: 0 AN: 35030

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36080

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3914

European-Non Finnish (NFE) AF: 0.000141 AC: 147 AN: 1041914

Other (OTH) AF: 0.00168 AC: 93 AN: 55498

GnomAD4 genome AF: 0.00573 AC: 873 AN: 152260 Hom.: 8 Cov.: 33 AF XY: 0.00522 AC XY: 389 AN XY: 74458

African (AFR) AF: 0.0190 AC: 789 AN: 41558

American (AMR) AF: 0.00255 AC: 39 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67988

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00434 Hom.: 0

Bravo AF: 0.00655

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		0.23
PromoterAI		-0.18	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs114874902; hg19: chr11-6411697;