rs775568984

Variant names:

• chr11-6390705-T-TGGC
• rs775568984
• NM_000543.5:c.108_109insGCG

Your query was ambiguous. Multiple possible variants found:

• chr11-6390705-T-TGGC
• chr11-6390705-T-TGGCGCTGGC
• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGC
• chr11-6390705-T-TGGCGCTGGCGCTGGC
• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGCGCTGGC
• chr11-6390705-T-TGGCGCTGGCGCTGGCGCTGGCGCTGGCGCTGGC

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM1 BP3 BP6_Very_Strong BS1 BS2

The NM_000543.5(SMPD1):​c.108_109insGCG​(p.Val36_Leu37insAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (5 hom., cov: 0)
  • Exomes 𝑓: 0.0048 (106 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMPD1 NM_000543.5 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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, G2P, PanelApp Australia, Genomics England PanelApp
• 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: Benign. The variant received -15 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-TGGC is Benign according to our data. Variant chr11-6390705-T-TGGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 529235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00526 (775/147350) while in subpopulation SAS AF = 0.0345 (160/4642). AF 95% confidence interval is 0.0301. There are 5 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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_109insGCG	p.Val36_Leu37insAla	conservative_inframe_insertion	Exon 1 of 6	NP_000534.3
	SMPD1	NM_001007593.3		c.108_109insGCG	p.Val36_Leu37insAla	conservative_inframe_insertion	Exon 1 of 6	NP_001007594.2	P17405-4
	SMPD1	NM_001365135.2		c.108_109insGCG	p.Val36_Leu37insAla	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_109insGCG	p.Val36_Leu37insAla	conservative_inframe_insertion	Exon 1 of 6	ENSP00000340409.4	P17405-1
	SMPD1	ENST00000531303.5	TSL:1	n.108_109insGCG		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1	E9PPK6
	SMPD1	ENST00000533123.5	TSL:1	n.108_109insGCG		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1	G3V1E1

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 777 AN: 147224 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00613

Gnomad ASJ AF: 0.00415

Gnomad EAS AF: 0.00878

Gnomad SAS AF: 0.0347

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.0204

Gnomad NFE AF: 0.00244

Gnomad OTH AF: 0.00149

GnomAD2 exomes AF: 0.00721 AC: 1724 AN: 238972 AF XY: 0.00793

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.00602

Gnomad EAS exome AF: 0.00595

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00200

Gnomad OTH exome AF: 0.00568

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00478 AC: 6924 AN: 1447752 Hom.: 106 Cov.: 0 AF XY: 0.00546 AC XY: 3931 AN XY: 720008

African (AFR) AF: 0.00302 AC: 100 AN: 33146

American (AMR) AF: 0.00701 AC: 311 AN: 44334

Ashkenazi Jewish (ASJ) AF: 0.00527 AC: 136 AN: 25808

East Asian (EAS) AF: 0.00694 AC: 274 AN: 39504

South Asian (SAS) AF: 0.0294 AC: 2508 AN: 85446

European-Finnish (FIN) AF: 0.0151 AC: 782 AN: 51776

Middle Eastern (MID) AF: 0.00545 AC: 31 AN: 5692

European-Non Finnish (NFE) AF: 0.00220 AC: 2428 AN: 1102376

Other (OTH) AF: 0.00593 AC: 354 AN: 59670

GnomAD4 genome AF: 0.00526 AC: 775 AN: 147350 Hom.: 5 Cov.: 0 AF XY: 0.00632 AC XY: 455 AN XY: 71996

African (AFR) AF: 0.00288 AC: 116 AN: 40212

American (AMR) AF: 0.00612 AC: 91 AN: 14864

Ashkenazi Jewish (ASJ) AF: 0.00415 AC: 14 AN: 3374

East Asian (EAS) AF: 0.00859 AC: 43 AN: 5004

South Asian (SAS) AF: 0.0345 AC: 160 AN: 4642

European-Finnish (FIN) AF: 0.0179 AC: 181 AN: 10136

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.00244 AC: 161 AN: 65926

Other (OTH) AF: 0.00147 AC: 3 AN: 2042

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Niemann-Pick disease, type A (1)
-	-	1	Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B (1)
-	-	1	not provided (1)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs775568984;

hg19: chr11-6411935;