chr8-58590041-C-T

Position:

• chr8-58590041-C-T

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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: 1.55

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 Likely_benign. Variant got -2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSMAF	NM_003580.4	c.2053G>A	p.Ala685Thr	missense_variant	25/31	ENST00000038176.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSMAF	ENST00000038176.8	c.2053G>A	p.Ala685Thr	missense_variant	25/31	1	NM_003580.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.2146G>A (p.A716T) alteration is located in exon 25 (coding exon 25) of the NSMAF gene. This alteration results from a G to A substitution at nucleotide position 2146, causing the alanine (A) at amino acid position 716 to be replaced by a threonine (T). 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	0.061
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;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.84	N;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.22	N;N
REVEL	Benign	0.082
Sift	Benign	0.49	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0	B;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-59502600; COSMIC: COSV50688290; COSMIC: COSV50688290;