Genetic Variant NSMAF:c.2447-55T>C (chr8-58586055-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003580.4(NSMAF):c.2447-55T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,360,804 control chromosomes in the GnomAD database, including 93,618 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.41 ( 13460 hom., cov: 32)

Exomes 𝑓: 0.36 ( 80158 hom. )

Consequence

NSMAF
NM_003580.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.66

Publications

6 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

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
NSMAF	NM_003580.4	MANE Select	c.2447-55T>C	intron	N/A	NP_003571.2
NSMAF	NM_001144772.1		c.2540-55T>C	intron	N/A	NP_001138244.1
NSMAF	NM_001413006.1		c.2516-55T>C	intron	N/A	NP_001399935.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NSMAF	ENST00000038176.8	TSL:1 MANE Select	c.2447-55T>C	intron	N/A	ENSP00000038176.3
NSMAF	ENST00000427130.7	TSL:2	c.2540-55T>C	intron	N/A	ENSP00000411012.2
NSMAF	ENST00000521972.1	TSL:5	n.122-55T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.408

AC:

62010

AN:

151880

Hom.:

13428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.554

Gnomad AMI

AF:

0.315

Gnomad AMR

AF:

0.302

Gnomad ASJ

AF:

0.296

Gnomad EAS

AF:

0.553

Gnomad SAS

AF:

0.411

Gnomad FIN

AF:

0.419

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.339

Gnomad OTH

AF:

0.382

GnomAD4 exome

AF:

0.359

AC:

434020

AN:

1208806

Hom.:

80158

AF XY:

0.361

AC XY:

221077

AN XY:

612228

show subpopulations

African (AFR)

AF:

0.562

AC:

16048

AN:

28540

American (AMR)

AF:

0.250

AC:

11076

AN:

44230

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

7313

AN:

24486

East Asian (EAS)

AF:

0.579

AC:

22250

AN:

38412

South Asian (SAS)

AF:

0.413

AC:

33565

AN:

81236

European-Finnish (FIN)

AF:

0.396

AC:

19636

AN:

49644

Middle Eastern (MID)

AF:

0.309

AC:

1641

AN:

5310

European-Non Finnish (NFE)

AF:

0.343

AC:

303573

AN:

884950

Other (OTH)

AF:

0.364

AC:

18918

AN:

51998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

14424

28849

43273

57698

72122

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9070

18140

27210

36280

45350

<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:

0.408

AC:

62081

AN:

151998

Hom.:

13460

Cov.:

AF XY:

0.411

AC XY:

30570

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.555

AC:

22979

AN:

41432

American (AMR)

AF:

0.302

AC:

4612

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

1026

AN:

3470

East Asian (EAS)

AF:

0.552

AC:

2852

AN:

5162

South Asian (SAS)

AF:

0.412

AC:

1988

AN:

4822

European-Finnish (FIN)

AF:

0.419

AC:

4422

AN:

10566

Middle Eastern (MID)

AF:

0.336

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.339

AC:

23025

AN:

67946

Other (OTH)

AF:

0.376

AC:

792

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1796

3593

5389

7186

8982

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.390

Hom.:

1552

Bravo

AF:

0.405

Asia WGS

AF:

0.447

AC:

1553

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.022

(source)

DANN

Benign

0.52

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over