chr17-46694639-A-G

Variant names:

• chr17-46694639-A-G
• NM_006178.4:c.1351A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_006178.4(NSF):​c.1351A>G​(p.Thr451Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006178.4
• PM2: Very rare variant in population databases, with high coverage

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.1351A>G	p.Thr451Ala	missense	Exon 12 of 21	NP_006169.2	P46459-1
	NSF	NR_040116.2		n.1418A>G		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.1351A>G	p.Thr451Ala	missense	Exon 12 of 21	ENSP00000381293.4	P46459-1
	NSF	ENST00000465370.2	TSL:5	c.1351A>G	p.Thr451Ala	missense	Exon 12 of 22	ENSP00000467779.2	K7EQD6
	NSF	ENST00000706392.1		c.1351A>G	p.Thr451Ala	missense	Exon 12 of 22	ENSP00000516369.1	P46459-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151032 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 24

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000132 AC: 2 AN: 151032 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 73752

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40452

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.37
Sift	Benign	0.097	T
Sift4G	Benign	0.15	T
Polyphen		0.60	P
Vest4		0.67
MutPred		0.33		Loss of MoRF binding (P = 0.1302)
MVP		0.82
MPC		2.4
ClinPred		0.96	D
GERP RS		3.9
Varity_R		0.22
gMVP		0.75

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

Other links and lift over

hg19: chr17-44772005;