Genetic Variant NSF:p.Thr344Met (chr17-46692988-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006178.4(NSF):c.1031C>T(p.Thr344Met) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NSF
NM_006178.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NSF	NM_006178.4 link	c.1031C>T	p.Thr344Met	missense_variant	Exon 10 of 21	ENST00000398238.8	NP_006169.2
NSF	NR_040116.2 link	n.1098C>T		non_coding_transcript_exon_variant	Exon 9 of 20
LRRC37A2	XM_024450773.2 link	c.4809+142469C>T		intron_variant	Intron 10 of 10		XP_024306541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSF	ENST00000398238.8 link	c.1031C>T	p.Thr344Met	missense_variant	Exon 10 of 21	1	NM_006178.4	ENSP00000381293.4		P46459-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

145882

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000274

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726864

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111628

Other (OTH)

AF:

0.00

AC:

AN:

60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000100134), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.363

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

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

AF:

0.00

AC:

AN:

145882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70452

African (AFR)

AF:

0.00

AC:

AN:

39266

American (AMR)

AF:

0.00

AC:

AN:

14314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

4874

South Asian (SAS)

AF:

0.00

AC:

AN:

4416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67122

Other (OTH)

AF:

0.00

AC:

AN:

1998

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1031C>T (p.T344M) alteration is located in exon 10 (coding exon 10) of the NSF gene. This alteration results from a C to T substitution at nucleotide position 1031, causing the threonine (T) at amino acid position 344 to be replaced by a methionine (M). 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

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.97

M_CAP

Pathogenic

0.44

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Benign

1.1

L;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.1

D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.61

MutPred

0.51

Loss of catalytic residue at T344 (P = 0.0218);.;

MVP

0.91

MPC

3.5

ClinPred

1.0

GERP RS

4.1

Varity_R

0.70

gMVP

0.57

Mutation Taster

=64/36

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over