chr17-46694654-C-T

Position:

• chr17-46694654-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006178.4(NSF):​c.1366C>T​(p.His456Tyr) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NSF. . Gene score misZ 2.584 (greater than the threshold 3.09). Trascript score misZ 3.1056 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy 96.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2540701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSF	NM_006178.4	c.1366C>T	p.His456Tyr	missense_variant	12/21	ENST00000398238.8	NP_006169.2
LRRC37A2	XM_024450773.2	c.4809+144135C>T		intron_variant			XP_024306541.1
NSF	NR_040116.2	n.1433C>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.1366C>T	p.His456Tyr	missense_variant	12/21	1	NM_006178.4	ENSP00000381293.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1353906 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 669852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.1366C>T (p.H456Y) alteration is located in exon 12 (coding exon 12) of the NSF gene. This alteration results from a C to T substitution at nucleotide position 1366, causing the histidine (H) at amino acid position 456 to be replaced by a tyrosine (Y). 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	Benign	0.31
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.081	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.83	N;.
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.51
MutPred		0.33		Loss of disorder (P = 0.046);.;
MVP		0.90
MPC		2.1
ClinPred		0.63	D
GERP RS		3.9
Varity_R		0.11
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-44772020;