Genetic Variant NSF:p.Ala430Val (chr17-46694577-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006178.4(NSF):c.1289C>T(p.Ala430Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NSF
NM_006178.4 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.89

Publications

0 publications found

Variant links:

Genes affected

NSF (HGNC:8016): (N-ethylmaleimide sensitive factor, vesicle fusing ATPase) Enables PDZ domain binding activity and ionotropic glutamate receptor binding activity. Involved in intracellular protein transport; positive regulation of protein catabolic process; and positive regulation of receptor recycling. Located in Golgi apparatus; cytosol; and plasma membrane. Implicated in developmental and epileptic encephalopathy. [provided by Alliance of Genome Resources, Apr 2022]

NSF links:

LRRC37A2 (HGNC:32404): (leucine rich repeat containing 37 member A2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LRRC37A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006178.4. 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
	NSF	NM_006178.4	MANE Select	c.1289C>T	p.Ala430Val	missense	Exon 12 of 21	NP_006169.2	P46459-1
	NSF	NR_040116.2		n.1356C>T		non_coding_transcript_exon	Exon 11 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NSF	ENST00000398238.8	TSL:1 MANE Select	c.1289C>T	p.Ala430Val	missense	Exon 12 of 21	ENSP00000381293.4	P46459-1
NSF	ENST00000465370.2	TSL:5	c.1289C>T	p.Ala430Val	missense	Exon 12 of 22	ENSP00000467779.2	K7EQD6
NSF	ENST00000706392.1		c.1289C>T	p.Ala430Val	missense	Exon 12 of 22	ENSP00000516369.1	P46459-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1269354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

634090

African (AFR)

AF:

0.00

AC:

AN:

25162

American (AMR)

AF:

0.00

AC:

AN:

35890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22716

East Asian (EAS)

AF:

0.00

AC:

AN:

37712

South Asian (SAS)

AF:

0.00

AC:

AN:

74276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5000

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

963894

Other (OTH)

AF:

0.00

AC:

AN:

53294

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:not provided

Revision:no classification provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.0

PhyloP100

7.9

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.78

MutPred

0.84

Loss of ubiquitination at K434 (P = 0.0771)

MVP

0.96

MPC

2.4

ClinPred

0.99

GERP RS

3.9

Varity_R

0.70

gMVP

0.94

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over