rs8164

Variant names:

• chr11-6394652-G-A
• rs8164
• NM_000543.5:c.*45G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000543.5(SMPD1):​c.*45G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,531,524 control chromosomes in the GnomAD database, including 16,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2501 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14454 hom.)
• Consequence: SMPD1 NM_000543.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.11
• Publications: 13 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-6394652-G-A is Benign according to our data. Variant chr11-6394652-G-A is described in ClinVar as Benign. ClinVar VariationId is 305208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

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.*45G>A		3_prime_UTR	Exon 6 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.*45G>A		3_prime_UTR	Exon 6 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.*45G>A		3_prime_UTR	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.*45G>A		3_prime_UTR	Exon 6 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000526280.1	TSL:1	c.*45G>A		3_prime_UTR	Exon 4 of 4	ENSP00000436278.1	H0YEP5
	SMPD1	ENST00000531303.5	TSL:1	n.*792G>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000432625.1	E9PPK6

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25286 AN: 152168 Hom.: 2493 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.131 AC: 28896 AN: 220964 AF XY: 0.133

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00402

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.139 AC: 191808 AN: 1379238 Hom.: 14454 Cov.: 22 AF XY: 0.140 AC XY: 96671 AN XY: 689874

African (AFR) AF: 0.278 AC: 8899 AN: 32064

American (AMR) AF: 0.0848 AC: 3711 AN: 43742

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 3289 AN: 25594

East Asian (EAS) AF: 0.00313 AC: 123 AN: 39268

South Asian (SAS) AF: 0.175 AC: 14790 AN: 84498

European-Finnish (FIN) AF: 0.107 AC: 4093 AN: 38104

Middle Eastern (MID) AF: 0.155 AC: 786 AN: 5058

European-Non Finnish (NFE) AF: 0.141 AC: 147980 AN: 1052950

Other (OTH) AF: 0.140 AC: 8137 AN: 57960

GnomAD4 genome AF: 0.166 AC: 25320 AN: 152286 Hom.: 2501 Cov.: 33 AF XY: 0.163 AC XY: 12174 AN XY: 74468

African (AFR) AF: 0.273 AC: 11358 AN: 41534

American (AMR) AF: 0.116 AC: 1777 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.160 AC: 771 AN: 4832

European-Finnish (FIN) AF: 0.0985 AC: 1046 AN: 10620

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9460 AN: 68018

Other (OTH) AF: 0.161 AC: 341 AN: 2112

Alfa AF: 0.147 Hom.: 3067

Bravo AF: 0.172

Asia WGS AF: 0.0850 AC: 294 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Niemann-Pick disease, type A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.61
PhyloP100		-1.1
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: rs8164; hg19: chr11-6415882;