17-46694654-CAC-TAT

Variant names:

• chr17-46694654-CAC-TAT
• NM_006178.4:c.1366_1368delCACinsTAT
• NSF p.His456Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS1_Moderate PP3

The NM_006178.4(NSF):​c.1366_1368delCACinsTAT​(p.His456Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 3 ACMG points.

• PS1: Transcript NM_006178.4 (NSF) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1366_1368delCACinsTAT	p.His456Tyr	missense	N/A	NP_006169.2	P46459-1
	NSF	NR_040116.2		n.1433_1435delCACinsTAT		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.1366_1368delCACinsTAT	p.His456Tyr	missense	N/A	ENSP00000381293.4	P46459-1
	NSF	ENST00000465370.2	TSL:5	c.1366_1368delCACinsTAT	p.His456Tyr	missense	N/A	ENSP00000467779.2	K7EQD6
	NSF	ENST00000706392.1		c.1366_1368delCACinsTAT	p.His456Tyr	missense	N/A	ENSP00000516369.1	P46459-1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-44772020;