8-58601546-GAAAAA-GAAAAAAAAA

Variant names:

• chr8-58601546-G-GAAAA
• rs33942423
• NM_003580.4:c.1126-15_1126-12dupTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003580.4(NSMAF):​c.1126-15_1126-12dupTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0835 in 1,399,740 control chromosomes in the GnomAD database, including 280 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 0)
  • Exomes 𝑓: 0.091 (246 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.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0134 (1810/135450) while in subpopulation SAS AF = 0.0459 (197/4288). AF 95% confidence interval is 0.0407. There are 34 homozygotes in GnomAd4. There are 871 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.1126-15_1126-12dupTTTT		intron	N/A	NP_003571.2
	NSMAF	NM_001144772.1		c.1219-15_1219-12dupTTTT		intron	N/A	NP_001138244.1	Q92636-2
	NSMAF	NM_001413006.1		c.1195-15_1195-12dupTTTT		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_1126-11insTTTT		intron	N/A	ENSP00000038176.3	Q92636-1
	NSMAF	ENST00000427130.7	TSL:2	c.1219-12_1219-11insTTTT		intron	N/A	ENSP00000411012.2	Q92636-2
	NSMAF	ENST00000958102.1		c.1147-12_1147-11insTTTT		intron	N/A	ENSP00000628161.1

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 1813 AN: 135432 Hom.: 34 Cov.: 0

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00944

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.0461

Gnomad FIN AF: 0.00432

Gnomad MID AF: 0.0321

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0118

GnomAD2 exomes AF: 0.0591 AC: 5991 AN: 101380 AF XY: 0.0571

Gnomad AFR exome AF: 0.0311

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.0595

Gnomad EAS exome AF: 0.0717

Gnomad FIN exome AF: 0.0241

Gnomad NFE exome AF: 0.0600

Gnomad OTH exome AF: 0.0680

GnomAD4 exome AF: 0.0910 AC: 115024 AN: 1264290 Hom.: 246 Cov.: 32 AF XY: 0.0910 AC XY: 56761 AN XY: 623816

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

African (AFR) AF: 0.0291 AC: 797 AN: 27370

American (AMR) AF: 0.107 AC: 2270 AN: 21248

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2125 AN: 19670

East Asian (EAS) AF: 0.0713 AC: 2397 AN: 33622

South Asian (SAS) AF: 0.105 AC: 6585 AN: 62552

European-Finnish (FIN) AF: 0.0508 AC: 2080 AN: 40912

Middle Eastern (MID) AF: 0.0798 AC: 354 AN: 4434

European-Non Finnish (NFE) AF: 0.0932 AC: 93439 AN: 1002186

Other (OTH) AF: 0.0952 AC: 4977 AN: 52296

⚠️ 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: 0.0134 AC: 1810 AN: 135450 Hom.: 34 Cov.: 0 AF XY: 0.0134 AC XY: 871 AN XY: 65172

African (AFR) AF: 0.00431 AC: 159 AN: 36880

American (AMR) AF: 0.00944 AC: 130 AN: 13776

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 102 AN: 3312

East Asian (EAS) AF: 0.00333 AC: 15 AN: 4500

South Asian (SAS) AF: 0.0459 AC: 197 AN: 4288

European-Finnish (FIN) AF: 0.00432 AC: 30 AN: 6944

Middle Eastern (MID) AF: 0.0310 AC: 8 AN: 258

European-Non Finnish (NFE) AF: 0.0183 AC: 1147 AN: 62804

Other (OTH) AF: 0.0117 AC: 22 AN: 1874

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

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

Other links and lift over

dbSNP: rs33942423; hg19: chr8-59514105;