NM_000543.5:c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG

Variant names:

• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGCGCTGGC
• rs775568984
• NM_000543.5:c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP3

The NM_000543.5(SMPD1):​c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG​(p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000543.5
• BP3: Nonframeshift variant in repetitive region in NM_000543.5

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.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 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.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCG		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147228 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000345 AC: 5 AN: 1447758 Hom.: 0 Cov.: 0 AF XY: 0.00000556 AC XY: 4 AN XY: 720014

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.0000226 AC: 1 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102378

Other (OTH) AF: 0.0000168 AC: 1 AN: 59670

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147354 Hom.: 0 Cov.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 71998

African (AFR) AF: 0.00 AC: 0 AN: 40212

American (AMR) AF: 0.0000673 AC: 1 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.000200 AC: 1 AN: 5004

South Asian (SAS) AF: 0.00 AC: 0 AN: 4642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65926

Other (OTH) AF: 0.00 AC: 0 AN: 2042

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs775568984; hg19: chr11-6411935;