Genetic Variant NM_003580.4: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).

Transcripts

RefSeq

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

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

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 v4.3

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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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