Genetic Variant NSMAF:c.1126-12delT (chr8-58601546-GA-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003580.4(NSMAF):c.1126-12delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,429,450 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0064 ( 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 2 ACMG points.

PM2

Variant has high frequency in the EAS (0.0139) population. However there is too low homozygotes in high coverage region: (expected more than 12, got 1).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003580.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NSMAF	NM_003580.4	MANE Select	c.1126-12delT	intron	N/A	NP_003571.2
NSMAF	NM_001144772.1		c.1219-12delT	intron	N/A	NP_001138244.1	Q92636-2
NSMAF	NM_001413006.1		c.1195-12delT	intron	N/A	NP_001399935.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NSMAF	ENST00000038176.8	TSL:1 MANE Select	c.1126-12delT	intron	N/A	ENSP00000038176.3	Q92636-1
NSMAF	ENST00000427130.7	TSL:2	c.1219-12delT	intron	N/A	ENSP00000411012.2	Q92636-2
NSMAF	ENST00000958102.1		c.1147-12delT	intron	N/A	ENSP00000628161.1

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

135458

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000726

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000231

Gnomad FIN

AF:

0.000865

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000143

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00644

AC:

8330

AN:

1293976

Hom.:

Cov.:

AF XY:

0.00679

AC XY:

4331

AN XY:

637916

show subpopulations

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

African (AFR)

AF:

0.00563

AC:

155

AN:

27524

American (AMR)

AF:

0.0101

AC:

218

AN:

21590

Ashkenazi Jewish (ASJ)

AF:

0.00999

AC:

201

AN:

20122

East Asian (EAS)

AF:

0.0150

AC:

507

AN:

33880

South Asian (SAS)

AF:

0.0133

AC:

840

AN:

63378

European-Finnish (FIN)

AF:

0.0146

AC:

597

AN:

40920

Middle Eastern (MID)

AF:

0.00909

AC:

AN:

4512

European-Non Finnish (NFE)

AF:

0.00526

AC:

5415

AN:

1028508

Other (OTH)

AF:

0.00665

AC:

356

AN:

53542

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

1062

2124

3185

4247

5309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

132

264

396

528

660

<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:

0.000295

AC:

AN:

135474

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

AN XY:

65186

show subpopulations

African (AFR)

AF:

0.000651

AC:

AN:

36884

American (AMR)

AF:

0.0000726

AC:

AN:

13780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3312

East Asian (EAS)

AF:

0.00

AC:

AN:

4504

South Asian (SAS)

AF:

0.00

AC:

AN:

4294

European-Finnish (FIN)

AF:

0.000865

AC:

AN:

6940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

258

European-Non Finnish (NFE)

AF:

0.000143

AC:

AN:

62816

Other (OTH)

AF:

0.00

AC:

AN:

1872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.419

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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.86

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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8-58601546-GAAAAA-GAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over