chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGC

Position:

• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000543.5(SMPD1):​c.108_109insGCGCTGGCGCTGGCGCTGGCG​(p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAla) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00010 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.158

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.108_109insGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAla	inframe_insertion	1/6	ENST00000342245.9	NP_000534.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMPD1	ENST00000342245.9	c.108_109insGCGCTGGCGCTGGCGCTGGCG	p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAla	inframe_insertion	1/6	1	NM_000543.5	ENSP00000340409	P3

Frequencies

GnomAD3 genomes AF: 0.0000340 AC: 5 AN: 147228 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000296

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.000216

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: 0.000103 AC: 149 AN: 1447758 Hom.: 0 Cov.: 0 AF XY: 0.0000931 AC XY: 67 AN XY: 720014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000354

Gnomad4 SAS exome AF: 0.000246

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.0000670

GnomAD4 genome AF: 0.0000340 AC: 5 AN: 147228 Hom.: 0 Cov.: 0 AF XY: 0.0000278 AC XY: 2 AN XY: 71866

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000296

Gnomad4 EAS AF: 0.000399

Gnomad4 SAS AF: 0.000216

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 661392). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.108_109insGCGCTGGCGCTGGCGCTGGCG, results in the insertion of 7 amino acid(s) of the SMPD1 protein (p.Val36_Leu37insAlaLeuAlaLeuAlaLeuAla), but otherwise preserves the integrity of the reading frame. -

Niemann-Pick disease, type A Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs775568984; hg19: chr11-6411935;