chr8-58601546-G-GAAAAAAAAAA

Variant names:

• chr8-58601545-AG-AGAAAAAAAAA
• NM_003580.4:c.1126-20_1126-12dupTTTTTTTTT

Variant summary

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

The NM_003580.4(NSMAF):​c.1126-20_1126-12dupTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. 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: 0.0000046 (1 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 0 ACMG points.

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.1126-20_1126-12dupTTTTTTTTT		intron	N/A	NP_003571.2
	NSMAF	NM_001144772.1		c.1219-20_1219-12dupTTTTTTTTT		intron	N/A	NP_001138244.1	Q92636-2
	NSMAF	NM_001413006.1		c.1195-20_1195-12dupTTTTTTTTT		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.1126-12_1126-11insTTTTTTTTT		intron	N/A	ENSP00000038176.3	Q92636-1
	NSMAF	ENST00000427130.7	TSL:2	c.1219-12_1219-11insTTTTTTTTT		intron	N/A	ENSP00000411012.2	Q92636-2
	NSMAF	ENST00000958102.1		c.1147-12_1147-11insTTTTTTTTT		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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000459 AC: 6 AN: 1308542 Hom.: 1 Cov.: 32 AF XY: 0.00000310 AC XY: 2 AN XY: 645418

⚠️ 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: 27762

American (AMR) AF: 0.0000459 AC: 1 AN: 21790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20340

East Asian (EAS) AF: 0.00 AC: 0 AN: 34608

South Asian (SAS) AF: 0.00 AC: 0 AN: 64204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4576

European-Non Finnish (NFE) AF: 0.00000481 AC: 5 AN: 1039442

Other (OTH) AF: 0.00 AC: 0 AN: 54114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000702897), 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: 65156

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

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-59514104;