rs199448

Variant names:

• chr17-46731635-A-G
• rs199448
• NM_006178.4:c.1908+2701A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006178.4(NSF):​c.1908+2701A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,166 control chromosomes in the GnomAD database, including 1,832 homozygotes. 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: 𝑓 0.13 (1832 hom., cov: 32)
• Consequence: NSF NM_006178.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 41 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSF	NM_006178.4	c.1908+2701A>G		intron_variant	Intron 17 of 20	ENST00000398238.8	NP_006169.2
NSF	NR_040116.2	n.1975+2701A>G		intron_variant	Intron 16 of 19
LRRC37A2	XM_024450773.2	c.4809+181116A>G		intron_variant	Intron 10 of 10		XP_024306541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSF	ENST00000398238.8	c.1908+2701A>G		intron_variant	Intron 17 of 20	1	NM_006178.4	ENSP00000381293.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20259 AN: 152048 Hom.: 1834 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.0721

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.133 AC: 20244 AN: 152166 Hom.: 1832 Cov.: 32 AF XY: 0.124 AC XY: 9256 AN XY: 74384

African (AFR) AF: 0.0361 AC: 1499 AN: 41554

American (AMR) AF: 0.163 AC: 2492 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 740 AN: 3466

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0599 AC: 289 AN: 4824

European-Finnish (FIN) AF: 0.0721 AC: 765 AN: 10606

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13812 AN: 67954

Other (OTH) AF: 0.166 AC: 349 AN: 2106

Alfa AF: 0.185 Hom.: 2019

Bravo AF: 0.138

Asia WGS AF: 0.0260 AC: 91 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.1
DANN	Benign	0.68
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs199448; hg19: chr17-44809001;