8-58601546-GAAAAA-GAAA

Variant names:

• chr8-58601546-GAA-G
• rs33942423
• NM_003580.4:c.1126-13_1126-12delTT

Variant summary

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

The NM_003580.4(NSMAF):​c.1126-13_1126-12delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,307,808 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000040 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NSMAF NM_003580.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMAF	NM_003580.4	MANE Select	c.1126-13_1126-12delTT		intron	N/A	NP_003571.2
	NSMAF	NM_001144772.1		c.1219-13_1219-12delTT		intron	N/A	NP_001138244.1	Q92636-2
	NSMAF	NM_001413006.1		c.1195-13_1195-12delTT		intron	N/A	NP_001399935.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMAF	ENST00000038176.8	TSL:1 MANE Select	c.1126-13_1126-12delTT		intron	N/A	ENSP00000038176.3	Q92636-1
	NSMAF	ENST00000427130.7	TSL:2	c.1219-13_1219-12delTT		intron	N/A	ENSP00000411012.2	Q92636-2
	NSMAF	ENST00000958102.1		c.1147-13_1147-12delTT		intron	N/A	ENSP00000628161.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 135476 Hom.: 0 Cov.: 0

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000398 AC: 52 AN: 1307808 Hom.: 0 AF XY: 0.0000388 AC XY: 25 AN XY: 645040

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

African (AFR) AF: 0.00 AC: 0 AN: 27756

American (AMR) AF: 0.0000460 AC: 1 AN: 21758

Ashkenazi Jewish (ASJ) AF: 0.0000984 AC: 2 AN: 20328

East Asian (EAS) AF: 0.0000579 AC: 2 AN: 34560

South Asian (SAS) AF: 0.000125 AC: 8 AN: 64116

European-Finnish (FIN) AF: 0.000168 AC: 7 AN: 41644

Middle Eastern (MID) AF: 0.000219 AC: 1 AN: 4574

European-Non Finnish (NFE) AF: 0.0000279 AC: 29 AN: 1038988

Other (OTH) AF: 0.0000370 AC: 2 AN: 54084

⚠️ 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.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 135476 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65154

African (AFR) AF: 0.00 AC: 0 AN: 36826

American (AMR) AF: 0.00 AC: 0 AN: 13768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3312

East Asian (EAS) AF: 0.00 AC: 0 AN: 4510

South Asian (SAS) AF: 0.00 AC: 0 AN: 4326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62832

Other (OTH) AF: 0.00 AC: 0 AN: 1862

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs33942423; hg19: chr8-59514105;