chr17-46694654-C-T

Variant names:

• chr17-46694654-C-T
• NM_006178.4:c.1366C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.89
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-46694654-C-T is Pathogenic according to our data. Variant chr17-46694654-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3408012.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2540701). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006178.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSF	NM_006178.4	MANE Select	c.1366C>T	p.His456Tyr	missense	Exon 12 of 21	NP_006169.2	P46459-1
	NSF	NR_040116.2		n.1433C>T		non_coding_transcript_exon	Exon 11 of 20

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSF	ENST00000398238.8	TSL:1 MANE Select	c.1366C>T	p.His456Tyr	missense	Exon 12 of 21	ENSP00000381293.4	P46459-1
	NSF	ENST00000465370.2	TSL:5	c.1366C>T	p.His456Tyr	missense	Exon 12 of 22	ENSP00000467779.2	K7EQD6
	NSF	ENST00000706392.1		c.1366C>T	p.His456Tyr	missense	Exon 12 of 22	ENSP00000516369.1	P46459-1

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

African (AFR) AF: 0.00 AC: 0 AN: 28332

American (AMR) AF: 0.00 AC: 0 AN: 33102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21712

East Asian (EAS) AF: 0.00 AC: 0 AN: 38690

South Asian (SAS) AF: 0.00 AC: 0 AN: 73370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5270

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1046186

Other (OTH) AF: 0.00 AC: 0 AN: 55992

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy 96 (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.83	N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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

Other links and lift over

hg19: chr17-44772020;