rs7951904

Variant names:

• chr11-6391701-T-C
• rs7951904
• NM_000543.5:c.636T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000543.5(SMPD1):​c.636T>C​(p.Asp212Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,561,480 control chromosomes in the GnomAD database, including 16,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1602 hom., cov: 29)
  • Exomes 𝑓: 0.14 (14468 hom.)
• Consequence: SMPD1 NM_000543.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.21
• Publications: 17 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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-6391701-T-C is Benign according to our data. Variant chr11-6391701-T-C is described in ClinVar as Benign. ClinVar VariationId is 93319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	NM_000543.5	MANE Select	c.636T>C	p.Asp212Asp	synonymous	Exon 2 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.633T>C	p.Asp211Asp	synonymous	Exon 2 of 6	NP_001007594.2
	SMPD1	NM_001365135.2		c.636T>C	p.Asp212Asp	synonymous	Exon 2 of 5	NP_001352064.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.636T>C	p.Asp212Asp	synonymous	Exon 2 of 6	ENSP00000340409.4
	SMPD1	ENST00000533123.5	TSL:1	n.636T>C		non_coding_transcript_exon	Exon 2 of 5	ENSP00000435950.1
	SMPD1	ENST00000534405.5	TSL:1	n.636T>C		non_coding_transcript_exon	Exon 2 of 6	ENSP00000434353.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 21308 AN: 141476 Hom.: 1599 Cov.: 29

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00254

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.150

GnomAD2 exomes AF: 0.124 AC: 30026 AN: 243056 AF XY: 0.127

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0771

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.00407

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.140 AC: 198651 AN: 1419896 Hom.: 14468 Cov.: 39 AF XY: 0.142 AC XY: 99918 AN XY: 706106

African (AFR) AF: 0.194 AC: 6284 AN: 32372

American (AMR) AF: 0.0844 AC: 3652 AN: 43264

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3353 AN: 24498

East Asian (EAS) AF: 0.00346 AC: 124 AN: 35800

South Asian (SAS) AF: 0.176 AC: 15097 AN: 85888

European-Finnish (FIN) AF: 0.112 AC: 5302 AN: 47480

Middle Eastern (MID) AF: 0.159 AC: 877 AN: 5514

European-Non Finnish (NFE) AF: 0.143 AC: 155859 AN: 1087330

Other (OTH) AF: 0.140 AC: 8103 AN: 57750

GnomAD4 genome AF: 0.151 AC: 21328 AN: 141584 Hom.: 1602 Cov.: 29 AF XY: 0.151 AC XY: 10274 AN XY: 68216

African (AFR) AF: 0.198 AC: 7567 AN: 38208

American (AMR) AF: 0.127 AC: 1649 AN: 13012

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 402 AN: 3414

East Asian (EAS) AF: 0.00255 AC: 11 AN: 4316

South Asian (SAS) AF: 0.174 AC: 757 AN: 4348

European-Finnish (FIN) AF: 0.118 AC: 1022 AN: 8684

Middle Eastern (MID) AF: 0.190 AC: 51 AN: 268

European-Non Finnish (NFE) AF: 0.142 AC: 9464 AN: 66470

Other (OTH) AF: 0.152 AC: 300 AN: 1980

Alfa AF: 0.138 Hom.: 3079

Bravo AF: 0.143

Asia WGS AF: 0.0780 AC: 270 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.144

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	3	Niemann-Pick disease, type A (3)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	Niemann-Pick disease, type B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		1.2
PromoterAI		0.023	Neutral
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: rs7951904; hg19: chr11-6412931; COSMIC: COSV54968709; COSMIC: COSV54968709;