Genetic Variant NM_006178.4:c.1471-19G>A (chr17-46710944-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006178.4(NSF):c.1471-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,567,776 control chromosomes in the GnomAD database, including 58,456 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 0.30 ( 7704 hom., cov: 32)

Exomes 𝑓: 0.25 ( 50752 hom. )

Consequence

NSF
NM_006178.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

104 publications found

Variant links:

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]

NSF links:

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]

LRRC37A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
NSF	NM_006178.4 link	c.1471-19G>A	intron_variant	Intron 13 of 20	ENST00000398238.8	NP_006169.2
NSF	NR_040116.2 link	n.1538-19G>A	intron_variant	Intron 12 of 19
LRRC37A2	XM_024450773.2 link	c.4809+160425G>A	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 link	c.1471-19G>A		intron_variant	Intron 13 of 20	1	NM_006178.4	ENSP00000381293.4		P46459-1

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45826

AN:

151970

Hom.:

7675

Cov.:

show subpopulations

Gnomad AFR

AF:

0.388

Gnomad AMI

AF:

0.334

Gnomad AMR

AF:

0.407

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.607

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.235

Gnomad OTH

AF:

0.312

GnomAD2 exomes

AF:

0.278

AC:

57912

AN:

208432

AF XY:

0.263

show subpopulations

Gnomad AFR exome

AF:

0.383

Gnomad AMR exome

AF:

0.502

Gnomad ASJ exome

AF:

0.286

Gnomad EAS exome

AF:

0.602

Gnomad FIN exome

AF:

0.150

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.251

AC:

355364

AN:

1415688

Hom.:

50752

Cov.:

AF XY:

0.247

AC XY:

173889

AN XY:

703696

show subpopulations

African (AFR)

AF:

0.396

AC:

12042

AN:

30424

American (AMR)

AF:

0.480

AC:

15442

AN:

32182

Ashkenazi Jewish (ASJ)

AF:

0.286

AC:

7176

AN:

25052

East Asian (EAS)

AF:

0.667

AC:

24508

AN:

36766

South Asian (SAS)

AF:

0.157

AC:

12208

AN:

77750

European-Finnish (FIN)

AF:

0.153

AC:

8154

AN:

53164

Middle Eastern (MID)

AF:

0.270

AC:

1333

AN:

4934

European-Non Finnish (NFE)

AF:

0.236

AC:

258720

AN:

1096856

Other (OTH)

AF:

0.269

AC:

15781

AN:

58560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

11527

23054

34580

46107

57634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9134

18268

27402

36536

45670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.302

AC:

45899

AN:

152088

Hom.:

7704

Cov.:

AF XY:

0.297

AC XY:

22112

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.389

AC:

16132

AN:

41468

American (AMR)

AF:

0.408

AC:

6234

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

976

AN:

3468

East Asian (EAS)

AF:

0.607

AC:

3132

AN:

5164

South Asian (SAS)

AF:

0.182

AC:

875

AN:

4820

European-Finnish (FIN)

AF:

0.143

AC:

1518

AN:

10590

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.235

AC:

15991

AN:

67986

Other (OTH)

AF:

0.310

AC:

654

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1591

3182

4772

6363

7954

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

442

884

1326

1768

2210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.264

Hom.:

20515

Bravo

AF:

0.335

Asia WGS

AF:

0.382

AC:

1325

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

8.6

(source)

DANN

Benign

0.60

PhyloP100

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over