8-58601498-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_003580.4(NSMAF):c.1163A>G(p.Tyr388Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000852 in 1,608,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
NSMAF
NM_003580.4 missense
NM_003580.4 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 6.13
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.974
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NSMAF | NM_003580.4 | c.1163A>G | p.Tyr388Cys | missense_variant | 15/31 | ENST00000038176.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NSMAF | ENST00000038176.8 | c.1163A>G | p.Tyr388Cys | missense_variant | 15/31 | 1 | NM_003580.4 | P1 | |
NSMAF | ENST00000427130.6 | c.1256A>G | p.Tyr419Cys | missense_variant | 15/31 | 2 | |||
NSMAF | ENST00000519858.1 | n.702A>G | non_coding_transcript_exon_variant | 8/9 | 3 | ||||
NSMAF | ENST00000649465.1 | c.*1289A>G | 3_prime_UTR_variant, NMD_transcript_variant | 17/33 |
Frequencies
GnomAD3 genomes ? AF: 0.0000542 AC: 8AN: 147630Hom.: 0 Cov.: 32
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?
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GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250336Hom.: 0 AF XY: 0.0000665 AC XY: 9AN XY: 135386
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GnomAD4 exome AF: 0.0000883 AC: 129AN: 1460998Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65AN XY: 726802
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GnomAD4 genome ? AF: 0.0000542 AC: 8AN: 147630Hom.: 0 Cov.: 32 AF XY: 0.0000280 AC XY: 2AN XY: 71448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2023 | The c.1256A>G (p.Y419C) alteration is located in exon 15 (coding exon 15) of the NSMAF gene. This alteration results from a A to G substitution at nucleotide position 1256, causing the tyrosine (Y) at amino acid position 419 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MVP
MPC
0.91
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at