8-58601546-G-GAAA

Variant names:

• chr8-58601546-G-GAAA
• rs33942423
• NM_003580.4:c.1126-14_1126-12dupTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003580.4(NSMAF):​c.1126-14_1126-12dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.43 (12890 hom., cov: 0)
  • Exomes 𝑓: 0.32 (6738 hom.)
  • Failed GnomAD Quality Control
• Consequence: NSMAF NM_003580.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 8-58601546-G-GAAA is Benign according to our data. Variant chr8-58601546-G-GAAA is described in ClinVar as Benign. ClinVar VariationId is 403262.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.431 AC: 58271 AN: 135098 Hom.: 12886 Cov.: 0

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.569

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.462

GnomAD2 exomes AF: 0.222 AC: 22497 AN: 101380 AF XY: 0.217

Gnomad AFR exome AF: 0.153

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.245

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.322 AC: 392723 AN: 1219316 Hom.: 6738 Cov.: 32 AF XY: 0.319 AC XY: 192245 AN XY: 602170

African (AFR) AF: 0.207 AC: 5464 AN: 26368

American (AMR) AF: 0.330 AC: 6898 AN: 20872

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 6462 AN: 19202

East Asian (EAS) AF: 0.294 AC: 9402 AN: 32014

South Asian (SAS) AF: 0.289 AC: 17695 AN: 61318

European-Finnish (FIN) AF: 0.230 AC: 9192 AN: 39892

Middle Eastern (MID) AF: 0.340 AC: 1482 AN: 4356

European-Non Finnish (NFE) AF: 0.332 AC: 319928 AN: 964746

Other (OTH) AF: 0.320 AC: 16200 AN: 50548

GnomAD4 genome AF: 0.431 AC: 58270 AN: 135116 Hom.: 12890 Cov.: 0 AF XY: 0.429 AC XY: 27906 AN XY: 65000

African (AFR) AF: 0.253 AC: 9327 AN: 36824

American (AMR) AF: 0.570 AC: 7819 AN: 13720

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1811 AN: 3304

East Asian (EAS) AF: 0.512 AC: 2293 AN: 4480

South Asian (SAS) AF: 0.493 AC: 2116 AN: 4288

European-Finnish (FIN) AF: 0.373 AC: 2573 AN: 6902

Middle Eastern (MID) AF: 0.527 AC: 135 AN: 256

European-Non Finnish (NFE) AF: 0.494 AC: 30964 AN: 62664

Other (OTH) AF: 0.463 AC: 864 AN: 1866

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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;