17-46694579-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_006178.4(NSF):c.1291G>A(p.Val431Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000689 in 1,434,514 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 22)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.41

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]

LRRC37A2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NSF
• BP4: Computational evidence support a benign effect (MetaRNN=0.024253935).
• BP6: Variant 17-46694579-G-A is Benign according to our data. Variant chr17-46694579-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2647865.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSF	NM_006178.4	c.1291G>A	p.Val431Met	missense_variant	12/21	ENST00000398238.8
LRRC37A2	XM_024450773.2	c.4809+144060G>A		intron_variant
NSF	NR_040116.2	n.1358G>A		non_coding_transcript_exon_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSF	ENST00000398238.8	c.1291G>A	p.Val431Met	missense_variant	12/21	1	NM_006178.4	P3

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 85 AN: 148390 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000424

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.000932

Gnomad OTH AF: 0.000493

GnomAD3 exomes AF: 0.000699 AC: 85 AN: 121546 Hom.: 0 AF XY: 0.000750 AC XY: 47 AN XY: 62648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.000307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.000702 AC: 903 AN: 1286032 Hom.: 3 Cov.: 19 AF XY: 0.000736 AC XY: 472 AN XY: 641606

Gnomad4 AFR exome AF: 0.000350

Gnomad4 AMR exome AF: 0.000972

Gnomad4 ASJ exome AF: 0.000746

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000583

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.000650

GnomAD4 genome AF: 0.000572 AC: 85 AN: 148482 Hom.: 0 Cov.: 22 AF XY: 0.000552 AC XY: 40 AN XY: 72408

Gnomad4 AFR AF: 0.000179

Gnomad4 AMR AF: 0.000529

Gnomad4 ASJ AF: 0.000581

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000424

Gnomad4 FIN AF: 0.0000949

Gnomad4 NFE AF: 0.000932

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000755 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000623 AC: 5

ExAC AF: 0.000464 AC: 55

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

NSF: PP2, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	15
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.024	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.67	N;.
REVEL	Benign	0.18
Sift	Uncertain	0.027	D;.
Sift4G	Uncertain	0.024	D;D
Polyphen		0.010	B;.
Vest4		0.17
MVP		0.53
MPC		1.9
ClinPred		0.022	T
GERP RS		0.73
Varity_R		0.049
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs373218599; hg19: chr17-44771945;