17-46749801-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_006178.4(NSF):c.1937C>G(p.Thr646Ser) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NSF NM_006178.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NSF
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSF	NM_006178.4	c.1937C>G	p.Thr646Ser	missense_variant	18/21	ENST00000398238.8
LRRC37A2	XM_024450773.2	c.4809+199282C>G		intron_variant
NSF	NR_040116.2	n.2004C>G		non_coding_transcript_exon_variant	17/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSF	ENST00000398238.8	c.1937C>G	p.Thr646Ser	missense_variant	18/21	1	NM_006178.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

NSF: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	21
Dann	Benign	0.75
DEOGEN2	Uncertain	0.55	D;T;T
Eigen	Benign	0.024
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.33	T;.;.
Sift4G	Benign	0.42	T;T;T
Polyphen		0.013	B;.;.
Vest4		0.37
MutPred		0.89		Gain of disorder (P = 0.0678);.;.;
MVP		0.77
MPC		0.53
ClinPred		0.69	D
GERP RS		5.4
Varity_R		0.13
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-44827167;