8-58601546-GAAAAA-GAAAAAAAAAAAA

Variant names:

• chr8-58601546-G-GAAAAAAA
• rs33942423
• NM_003580.4:c.1126-18_1126-12dupTTTTTTT

Variant summary

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

The NM_003580.4(NSMAF):​c.1126-18_1126-12dupTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,308,408 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: not found (cov: 0)
  • Exomes 𝑓: 0.000049 (0 hom.)
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMAF	NM_003580.4	c.1126-18_1126-12dupTTTTTTT		intron_variant	Intron 14 of 30	ENST00000038176.8	NP_003571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMAF	ENST00000038176.8	c.1126-18_1126-12dupTTTTTTT		intron_variant	Intron 14 of 30	1	NM_003580.4	ENSP00000038176.3
NSMAF	ENST00000427130.7	c.1219-18_1219-12dupTTTTTTT		intron_variant	Intron 14 of 30	2		ENSP00000411012.2
NSMAF	ENST00000519858.1	n.665-18_665-12dupTTTTTTT		intron_variant	Intron 7 of 8	3
NSMAF	ENST00000649465.1	n.*1252-18_*1252-12dupTTTTTTT		intron_variant	Intron 16 of 32			ENSP00000498107.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.0000489 AC: 64 AN: 1308408 Hom.: 0 Cov.: 32 AF XY: 0.0000604 AC XY: 39 AN XY: 645346

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

African (AFR) AF: 0.000108 AC: 3 AN: 27764

American (AMR) AF: 0.0000918 AC: 2 AN: 21782

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

East Asian (EAS) AF: 0.0000578 AC: 2 AN: 34606

South Asian (SAS) AF: 0.000312 AC: 20 AN: 64180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41700

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

European-Non Finnish (NFE) AF: 0.0000337 AC: 35 AN: 1039364

Other (OTH) AF: 0.0000370 AC: 2 AN: 54096

⚠️ 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.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.86

Splicing

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

Other links and lift over

dbSNP: rs33942423; hg19: chr8-59514105;