17-46713956-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006178.4(NSF):c.1731T>C(p.Ser577=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00595 in 1,606,030 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (35 hom.)
• Consequence: NSF NM_006178.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.240

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 17-46713956-T-C is Benign according to our data. Variant chr17-46713956-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 775110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.24 with no splicing effect.
• BS2: High AC in GnomAd at 670 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSF	NM_006178.4	c.1731T>C	p.Ser577=	synonymous_variant	15/21	ENST00000398238.8
LRRC37A2	XM_024450773.2	c.4809+163437T>C		intron_variant
NSF	NR_040116.2	n.1798T>C		non_coding_transcript_exon_variant	14/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSF	ENST00000398238.8	c.1731T>C	p.Ser577=	synonymous_variant	15/21	1	NM_006178.4	P3

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 670 AN: 152202 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00631

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00418 AC: 1005 AN: 240186 Hom.: 3 AF XY: 0.00448 AC XY: 583 AN XY: 130120

Gnomad AFR exome AF: 0.000783

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00802

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00435

Gnomad FIN exome AF: 0.000652

Gnomad NFE exome AF: 0.00624

Gnomad OTH exome AF: 0.00287

GnomAD4 exome AF: 0.00612 AC: 8894 AN: 1453710 Hom.: 35 Cov.: 31 AF XY: 0.00612 AC XY: 4426 AN XY: 722662

Gnomad4 AFR exome AF: 0.000878

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00511

Gnomad4 FIN exome AF: 0.000787

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.00439 AC: 668 AN: 152320 Hom.: 8 Cov.: 32 AF XY: 0.00448 AC XY: 334 AN XY: 74508

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00631

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00605 Hom.: 10

Bravo AF: 0.00402

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	NSF: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	8.6
Dann	Benign	0.70

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: rs11537609; hg19: chr17-44791322;