8-58585667-T-C

Variant names:

• chr8-58585667-T-C
• NM_003580.4:c.2644A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003580.4(NSMAF):​c.2644A>G​(p.Ile882Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSMAF NM_003580.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14110214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSMAF	NM_003580.4	c.2644A>G	p.Ile882Val	missense_variant	Exon 30 of 31	ENST00000038176.8	NP_003571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSMAF	ENST00000038176.8	c.2644A>G	p.Ile882Val	missense_variant	Exon 30 of 31	1	NM_003580.4	ENSP00000038176.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2737A>G (p.I913V) alteration is located in exon 30 (coding exon 30) of the NSMAF gene. This alteration results from a A to G substitution at nucleotide position 2737, causing the isoleucine (I) at amino acid position 913 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.082	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.080
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.086
Sift	Benign	0.28	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.015	B;B
Vest4		0.20
MutPred		0.68		Loss of ubiquitination at K877 (P = 0.1264);.;
MVP		0.38
MPC		0.28
ClinPred		0.53	D
GERP RS		5.6
Varity_R		0.045
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-59498226;