11-6390705-T-TGGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC

Variant names:

• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC
• rs775568984
• NM_000543.5:c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCG

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_109insGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCG​(p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAlaLeuAla) 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 0.0000068 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0000083 (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: 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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.108_109insGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAlaLeuAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.00000679 AC: 1 AN: 147228 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000829 AC: 12 AN: 1447756 Hom.: 0 Cov.: 0 AF XY: 0.0000139 AC XY: 10 AN XY: 720012

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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: 0.000105 AC: 9 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: 0.00000272 AC: 3 AN: 1102376

Other (OTH) AF: 0.00 AC: 0 AN: 59670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000101), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000679 AC: 1 AN: 147228 Hom.: 0 Cov.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 71866

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40092

American (AMR) AF: 0.00 AC: 0 AN: 14846

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.00 AC: 0 AN: 4640

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65934

Other (OTH) AF: 0.00 AC: 0 AN: 2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;