8-58601546-GAAAAA-GAAAAAA

Variant names:

• chr8-58601546-G-GA
• rs33942423
• NM_003580.4:c.1126-12dupT

Variant summary

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

The NM_003580.4(NSMAF):​c.1126-12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0911 in 1,386,626 control chromosomes in the GnomAD database, including 761 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.065 (402 hom., cov: 0)
  • Exomes 𝑓: 0.094 (359 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 = 0.116 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMAF	NM_003580.4	MANE Select	c.1126-12dupT		intron	N/A	NP_003571.2
	NSMAF	NM_001144772.1		c.1219-12dupT		intron	N/A	NP_001138244.1	Q92636-2
	NSMAF	NM_001413006.1		c.1195-12dupT		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_1126-11insT		intron	N/A	ENSP00000038176.3	Q92636-1
	NSMAF	ENST00000427130.7	TSL:2	c.1219-12_1219-11insT		intron	N/A	ENSP00000411012.2	Q92636-2
	NSMAF	ENST00000958102.1		c.1147-12_1147-11insT		intron	N/A	ENSP00000628161.1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 8812 AN: 135386 Hom.: 402 Cov.: 0

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0737

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0139

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00717

Gnomad FIN AF: 0.0789

Gnomad MID AF: 0.0536

Gnomad NFE AF: 0.0487

Gnomad OTH AF: 0.0576

GnomAD2 exomes AF: 0.160 AC: 16219 AN: 101380 AF XY: 0.164

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.0939 AC: 117475 AN: 1251222 Hom.: 359 Cov.: 32 AF XY: 0.0944 AC XY: 58293 AN XY: 617392

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

African (AFR) AF: 0.154 AC: 4114 AN: 26630

American (AMR) AF: 0.0859 AC: 1825 AN: 21246

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 1249 AN: 19790

East Asian (EAS) AF: 0.0936 AC: 3044 AN: 32530

South Asian (SAS) AF: 0.0758 AC: 4699 AN: 61998

European-Finnish (FIN) AF: 0.142 AC: 5689 AN: 39982

Middle Eastern (MID) AF: 0.0811 AC: 359 AN: 4424

European-Non Finnish (NFE) AF: 0.0924 AC: 91757 AN: 992846

Other (OTH) AF: 0.0915 AC: 4739 AN: 51776

⚠️ 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 AF: 0.0651 AC: 8817 AN: 135404 Hom.: 402 Cov.: 0 AF XY: 0.0642 AC XY: 4184 AN XY: 65138

African (AFR) AF: 0.119 AC: 4376 AN: 36864

American (AMR) AF: 0.0418 AC: 576 AN: 13766

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 46 AN: 3308

East Asian (EAS) AF: 0.00133 AC: 6 AN: 4502

South Asian (SAS) AF: 0.00722 AC: 31 AN: 4296

European-Finnish (FIN) AF: 0.0789 AC: 547 AN: 6936

Middle Eastern (MID) AF: 0.0581 AC: 15 AN: 258

European-Non Finnish (NFE) AF: 0.0486 AC: 3053 AN: 62790

Other (OTH) AF: 0.0572 AC: 107 AN: 1870

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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;