8-58601546-GAAAAA-GAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_003580.4(NSMAF):​c.1126-13_1126-12dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 1,406,474 control chromosomes in the GnomAD database, including 3,168 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1904 hom., cov: 0)
  • Exomes 𝑓: 0.094 (1264 hom.)
• Consequence: NSMAF NM_003580.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.861
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMAF	NM_003580.4	c.1126-13_1126-12dupTT		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.1126-13_1126-12dupTT		intron_variant	Intron 14 of 30	1	NM_003580.4	ENSP00000038176.3
NSMAF	ENST00000427130.7	c.1219-13_1219-12dupTT		intron_variant	Intron 14 of 30	2		ENSP00000411012.2
NSMAF	ENST00000519858.1	n.665-13_665-12dupTT		intron_variant	Intron 7 of 8	3
NSMAF	ENST00000649465.1	n.*1252-13_*1252-12dupTT		intron_variant	Intron 16 of 32			ENSP00000498107.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 18012 AN: 135374 Hom.: 1903 Cov.: 0

Gnomad AFR AF: 0.295

Gnomad AMI AF: 0.0369

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00665

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0821

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.112

GnomAD2 exomes AF: 0.121 AC: 12276 AN: 101380 AF XY: 0.118

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0587

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.0943 AC: 119894 AN: 1271080 Hom.: 1264 Cov.: 32 AF XY: 0.0937 AC XY: 58769 AN XY: 627052

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

African (AFR) AF: 0.256 AC: 6885 AN: 26894

American (AMR) AF: 0.109 AC: 2312 AN: 21190

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2305 AN: 19692

East Asian (EAS) AF: 0.0386 AC: 1298 AN: 33612

South Asian (SAS) AF: 0.0965 AC: 6056 AN: 62750

European-Finnish (FIN) AF: 0.0902 AC: 3676 AN: 40768

Middle Eastern (MID) AF: 0.104 AC: 462 AN: 4444

European-Non Finnish (NFE) AF: 0.0908 AC: 91626 AN: 1009198

Other (OTH) AF: 0.100 AC: 5274 AN: 52532

⚠️ 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 AF: 0.133 AC: 18026 AN: 135394 Hom.: 1904 Cov.: 0 AF XY: 0.131 AC XY: 8552 AN XY: 65142

African (AFR) AF: 0.295 AC: 10877 AN: 36818

American (AMR) AF: 0.0753 AC: 1037 AN: 13774

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 338 AN: 3310

East Asian (EAS) AF: 0.00666 AC: 30 AN: 4504

South Asian (SAS) AF: 0.0739 AC: 317 AN: 4292

European-Finnish (FIN) AF: 0.0663 AC: 460 AN: 6940

Middle Eastern (MID) AF: 0.0930 AC: 24 AN: 258

European-Non Finnish (NFE) AF: 0.0749 AC: 4706 AN: 62810

Other (OTH) AF: 0.110 AC: 207 AN: 1874

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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; COSMIC: COSV50703813; COSMIC: COSV50703813;