Genetic Variant NM_000543.5:c.126_143dupGCTGGCGCTGGCGCTGGC (chr11-6390705-T-TGCTGGCGCTGGCGCTGGC) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_000543.5(SMPD1):c.126_143dupGCTGGCGCTGGCGCTGGC(p.Ala48_Leu49insLeuAlaLeuAlaLeuAla) variant causes a disruptive 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. Synonymous variant affecting the same amino acid position (i.e. A48A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SMPD1
NM_000543.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.158

Publications

17 publications found

Variant links:

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)

SMPD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	NM_000543.5	MANE Select	c.126_143dupGCTGGCGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAlaLeuAla	disruptive_inframe_insertion	Exon 1 of 6	NP_000534.3
SMPD1	NM_001007593.3		c.126_143dupGCTGGCGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAlaLeuAla	disruptive_inframe_insertion	Exon 1 of 6	NP_001007594.2
SMPD1	NM_001365135.2		c.126_143dupGCTGGCGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAlaLeuAla	disruptive_inframe_insertion	Exon 1 of 5	NP_001352064.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMPD1	ENST00000342245.9	TSL:1 MANE Select	c.126_143dupGCTGGCGCTGGCGCTGGC	p.Ala48_Leu49insLeuAlaLeuAlaLeuAla	disruptive_inframe_insertion	Exon 1 of 6	ENSP00000340409.4
SMPD1	ENST00000531303.5	TSL:1	n.126_143dupGCTGGCGCTGGCGCTGGC		non_coding_transcript_exon	Exon 1 of 6	ENSP00000432625.1
SMPD1	ENST00000533123.5	TSL:1	n.126_143dupGCTGGCGCTGGCGCTGGC		non_coding_transcript_exon	Exon 1 of 5	ENSP00000435950.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447758

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33148

American (AMR)

AF:

0.00

AC:

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25808

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00

AC:

AN:

85446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102378

Other (OTH)

AF:

0.0000168

AC:

AN:

59670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.16

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over