Genetic Variant NSMAF:c.1126-16_1126-12dupTTTTT (chr8-58601546-G-GAAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003580.4(NSMAF):c.1126-16_1126-12dupTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,436,226 control chromosomes in the GnomAD database, including 13 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000081 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0037 ( 12 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: Likely_benign. The variant received -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0000812

AC:

AN:

135474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000272

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000159

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00810

AC:

821

AN:

101380

AF XY:

0.00771

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.00776

Gnomad EAS exome

AF:

0.00962

Gnomad FIN exome

AF:

0.00265

Gnomad NFE exome

AF:

0.00844

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.00367

AC:

4773

AN:

1300752

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

2482

AN XY:

641440

show subpopulations

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

African (AFR)

AF:

0.00141

AC:

AN:

27732

American (AMR)

AF:

0.00782

AC:

169

AN:

21602

Ashkenazi Jewish (ASJ)

AF:

0.00639

AC:

129

AN:

20178

East Asian (EAS)

AF:

0.00311

AC:

107

AN:

34448

South Asian (SAS)

AF:

0.0108

AC:

690

AN:

63650

European-Finnish (FIN)

AF:

0.00243

AC:

101

AN:

41548

Middle Eastern (MID)

AF:

0.00418

AC:

AN:

4546

European-Non Finnish (NFE)

AF:

0.00319

AC:

3292

AN:

1033264

Other (OTH)

AF:

0.00422

AC:

227

AN:

53784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.296

Heterozygous variant carriers

382

765

1147

1530

1912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000812

AC:

AN:

135474

Hom.:

Cov.:

AF XY:

0.0000614

AC XY:

AN XY:

65152

show subpopulations

African (AFR)

AF:

0.0000272

AC:

AN:

36826

American (AMR)

AF:

0.00

AC:

AN:

13766

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:

0.00

AC:

AN:

6946

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.000159

AC:

AN:

62832

Other (OTH)

AF:

0.00

AC:

AN:

1862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.86

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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8-58601546-GAAAAA-GAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over