11-6390705-T-TGGCGCTGGC

Variant names:

• chr11-6390705-T-TGGCGCTGGC
• rs775568984
• NM_000543.5:c.108_109insGCGCTGGCG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP3 BP6_Moderate BS2

The NM_000543.5(SMPD1):​c.108_109insGCGCTGGCG​(p.Val36_Leu37insAlaLeuAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (19 hom., cov: 0)
  • Exomes 𝑓: 0.014 (173 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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: Likely_benign. The variant received -5 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
• BP6: Variant 11-6390705-T-TGGCGCTGGC is Benign according to our data. Variant chr11-6390705-T-TGGCGCTGGC is described in ClinVar as Benign. ClinVar VariationId is 1170921.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD1	NM_000543.5	c.108_109insGCGCTGGCG	p.Val36_Leu37insAlaLeuAla	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_109insGCGCTGGCG	p.Val36_Leu37insAlaLeuAla	conservative_inframe_insertion	Exon 1 of 6	1	NM_000543.5	ENSP00000340409.4

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1625 AN: 147226 Hom.: 19 Cov.: 0

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.0763

Gnomad AMR AF: 0.00519

Gnomad ASJ AF: 0.000593

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.0136

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.00941

GnomAD2 exomes AF: 0.0115 AC: 2742 AN: 238972 AF XY: 0.0119

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.000816

Gnomad EAS exome AF: 0.00992

Gnomad FIN exome AF: 0.0212

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.0108

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0135 AC: 19560 AN: 1447704 Hom.: 173 Cov.: 0 AF XY: 0.0134 AC XY: 9671 AN XY: 719976

African (AFR) AF: 0.00211 AC: 70 AN: 33146

American (AMR) AF: 0.00363 AC: 161 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 26 AN: 25808

East Asian (EAS) AF: 0.00785 AC: 310 AN: 39504

South Asian (SAS) AF: 0.0149 AC: 1270 AN: 85440

European-Finnish (FIN) AF: 0.0285 AC: 1477 AN: 51766

Middle Eastern (MID) AF: 0.00720 AC: 41 AN: 5692

European-Non Finnish (NFE) AF: 0.0141 AC: 15546 AN: 1102350

Other (OTH) AF: 0.0110 AC: 659 AN: 59664

GnomAD4 genome AF: 0.0110 AC: 1626 AN: 147352 Hom.: 19 Cov.: 0 AF XY: 0.0117 AC XY: 841 AN XY: 71996

African (AFR) AF: 0.00313 AC: 126 AN: 40212

American (AMR) AF: 0.00518 AC: 77 AN: 14866

Ashkenazi Jewish (ASJ) AF: 0.000593 AC: 2 AN: 3374

East Asian (EAS) AF: 0.0102 AC: 51 AN: 5004

South Asian (SAS) AF: 0.0146 AC: 68 AN: 4642

European-Finnish (FIN) AF: 0.0357 AC: 362 AN: 10136

Middle Eastern (MID) AF: 0.0184 AC: 5 AN: 272

European-Non Finnish (NFE) AF: 0.0129 AC: 849 AN: 65926

Other (OTH) AF: 0.00930 AC: 19 AN: 2042

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type A Benign:1

Aug 09, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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;