Genetic Variant NSMAF:c.1126-25_1126-12dupTTTTTTTTTTTTTT (chr8-58601546-G-GAAAAAAAAAAAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003580.4(NSMAF):c.1126-25_1126-12dupTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,444,030 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000074 ( 0 hom., cov: 0)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

NSMAF
NM_003580.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.861

Publications

1 publications found

Variant links:

Genes affected

NSMAF (HGNC:8017): (neutral sphingomyelinase activation associated factor) This gene encodes a WD-repeat protein that binds the cytoplasmic sphingomyelinase activation domain of the 55kD tumor necrosis factor receptor. This protein is required for TNF-mediated activation of neutral sphingomyelinase and may play a role in regulating TNF-induced cellular responses such as inflammation. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2009]

NSMAF links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMAF	NM_003580.4 link	c.1126-25_1126-12dupTTTTTTTTTTTTTT		intron_variant	Intron 14 of 30	ENST00000038176.8	NP_003571.2	Q92636-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NSMAF	ENST00000038176.8 link	c.1126-25_1126-12dupTTTTTTTTTTTTTT	intron_variant	Intron 14 of 30	1	NM_003580.4	ENSP00000038176.3	Q92636-1
NSMAF	ENST00000427130.7 link	c.1219-25_1219-12dupTTTTTTTTTTTTTT	intron_variant	Intron 14 of 30	2		ENSP00000411012.2	Q92636-2
NSMAF	ENST00000519858.1 link	n.665-25_665-12dupTTTTTTTTTTTTTT	intron_variant	Intron 7 of 8	3
NSMAF	ENST00000649465.1 link	n.1252-25_1252-12dupTTTTTTTTTTTTTT	intron_variant	Intron 16 of 32			ENSP00000498107.1	E5RGU2

Frequencies

GnomAD3 genomes

AF:

0.00000738

AC:

AN:

135478

Hom.:

Cov.:

show subpopulations

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:

0.000144

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.64e-7

AC:

AN:

1308552

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

645424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27764

American (AMR)

AF:

0.00

AC:

AN:

21790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20340

East Asian (EAS)

AF:

0.00

AC:

AN:

34608

South Asian (SAS)

AF:

0.0000156

AC:

AN:

64204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4578

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1039448

Other (OTH)

AF:

0.00

AC:

AN:

54114

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

AF:

0.00000738

AC:

AN:

135478

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

65156

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

36826

American (AMR)

AF:

0.00

AC:

AN:

13768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3312

East Asian (EAS)

AF:

0.00

AC:

AN:

4510

South Asian (SAS)

AF:

0.00

AC:

AN:

4326

European-Finnish (FIN)

AF:

0.000144

AC:

AN:

6946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62834

Other (OTH)

AF:

0.00

AC:

AN:

1862

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.86

Splicing

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

Publications

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8-58601546-GAAAAA-GAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over