8-58590041-C-T

Variant names:

• chr8-58590041-C-T
• rs1805986320
• NM_003580.4:c.2053G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003580.4(NSMAF):​c.2053G>A​(p.Ala685Thr) 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. 16/22 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: 1.55
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042966157).

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.2053G>A	p.Ala685Thr	missense	Exon 25 of 31	NP_003571.2
	NSMAF	NM_001144772.1		c.2146G>A	p.Ala716Thr	missense	Exon 25 of 31	NP_001138244.1	Q92636-2
	NSMAF	NM_001413006.1		c.2122G>A	p.Ala708Thr	missense	Exon 26 of 32	NP_001399935.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSMAF	ENST00000038176.8	TSL:1 MANE Select	c.2053G>A	p.Ala685Thr	missense	Exon 25 of 31	ENSP00000038176.3	Q92636-1
	NSMAF	ENST00000427130.7	TSL:2	c.2146G>A	p.Ala716Thr	missense	Exon 25 of 31	ENSP00000411012.2	Q92636-2
	NSMAF	ENST00000958102.1		c.2074G>A	p.Ala692Thr	missense	Exon 25 of 31	ENSP00000628161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.84	N
PhyloP100		1.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.082
Sift	Benign	0.49	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.34		Gain of glycosylation at A685 (P = 0.0731)
MVP		0.12
MPC		0.21
ClinPred		0.44	T
GERP RS		0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.19
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1805986320; hg19: chr8-59502600; COSMIC: COSV50688290; COSMIC: COSV50688290;