17-46694563-C-T

Position:

• chr17-46694563-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_006178.4(NSF):​c.1275C>T​(p.Asp425Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (1 hom., cov: 22)
  • Exomes 𝑓: 0.0057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NSF NM_006178.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.611

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

NSF (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 17-46694563-C-T is Benign according to our data. Variant chr17-46694563-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1335280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.611 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSF	NM_006178.4	c.1275C>T	p.Asp425Asp	synonymous_variant	12/21	ENST00000398238.8	NP_006169.2
LRRC37A2	XM_024450773.2	c.4809+144044C>T		intron_variant			XP_024306541.1
NSF	NR_040116.2	n.1342C>T		non_coding_transcript_exon_variant	11/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSF	ENST00000398238.8	c.1275C>T	p.Asp425Asp	synonymous_variant	12/21	1	NM_006178.4	ENSP00000381293.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 852 AN: 145712 Hom.: 1 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0465

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00526

Gnomad EAS AF: 0.000643

Gnomad SAS AF: 0.00302

Gnomad FIN AF: 0.00202

Gnomad MID AF: 0.0166

Gnomad NFE AF: 0.00841

Gnomad OTH AF: 0.00400

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00572 AC: 6898 AN: 1205884 Hom.: 0 Cov.: 17 AF XY: 0.00558 AC XY: 3385 AN XY: 606566

Gnomad4 AFR exome AF: 0.00139

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00374

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00590

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00584 AC: 852 AN: 145808 Hom.: 1 Cov.: 22 AF XY: 0.00575 AC XY: 409 AN XY: 71100

Gnomad4 AFR AF: 0.00223

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.00526

Gnomad4 EAS AF: 0.000645

Gnomad4 SAS AF: 0.00302

Gnomad4 FIN AF: 0.00202

Gnomad4 NFE AF: 0.00841

Gnomad4 OTH AF: 0.00396

Alfa AF: 0.00539 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	NSF: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.0
DANN	Benign	0.32

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: rs369349043; hg19: chr17-44771929;