rs35098198

Variant names:

• chr11-6394460-G-A
• rs35098198
• NM_000543.5:c.1749G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-6394460-G-A
• chr11-6394460-G-C
• chr11-6394460-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000543.5(SMPD1):​c.1749G>A​(p.Ser583Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,614,050 control chromosomes in the GnomAD database, including 439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (27 hom., cov: 33)
  • Exomes 𝑓: 0.022 (412 hom.)
• Consequence: SMPD1 NM_000543.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.39
• Publications: 7 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: Orphanet, Genomics England PanelApp, PanelApp Australia, G2P
• Niemann-Pick disease type B

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant 11-6394460-G-A is Benign according to our data. Variant chr11-6394460-G-A is described in ClinVar as Benign. ClinVar VariationId is 256593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0169 (2571/152254) while in subpopulation NFE AF = 0.0232 (1580/68016). AF 95% confidence interval is 0.0223. There are 27 homozygotes in GnomAd4. There are 1270 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000543.5. 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
	SMPD1	NM_000543.5	MANE Select	c.1749G>A	p.Ser583Ser	synonymous	Exon 6 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.1746G>A	p.Ser582Ser	synonymous	Exon 6 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.1617G>A	p.Ser539Ser	synonymous	Exon 5 of 5	NP_001352064.1	P17405-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.1749G>A	p.Ser583Ser	synonymous	Exon 6 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.804G>A	p.Ser268Ser	synonymous	Exon 4 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*600G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2575 AN: 152134 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0195 AC: 4903 AN: 251302 AF XY: 0.0208

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.0106

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0397

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0222 AC: 32457 AN: 1461796 Hom.: 412 Cov.: 34 AF XY: 0.0222 AC XY: 16145 AN XY: 727196

African (AFR) AF: 0.00343 AC: 115 AN: 33480

American (AMR) AF: 0.0112 AC: 499 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 535 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0210 AC: 1808 AN: 86258

European-Finnish (FIN) AF: 0.0378 AC: 2014 AN: 53330

Middle Eastern (MID) AF: 0.0227 AC: 131 AN: 5768

European-Non Finnish (NFE) AF: 0.0235 AC: 26170 AN: 1112008

Other (OTH) AF: 0.0196 AC: 1181 AN: 60392

GnomAD4 genome AF: 0.0169 AC: 2571 AN: 152254 Hom.: 27 Cov.: 33 AF XY: 0.0171 AC XY: 1270 AN XY: 74434

African (AFR) AF: 0.00407 AC: 169 AN: 41568

American (AMR) AF: 0.0127 AC: 195 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4822

European-Finnish (FIN) AF: 0.0392 AC: 415 AN: 10598

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1580 AN: 68016

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0198 Hom.: 56

Bravo AF: 0.0145

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Niemann-Pick disease, type A (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.51
DANN	Benign	0.87
PhyloP100		-3.4
Mutation Taster		=98/2	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: rs35098198; hg19: chr11-6415690;