Genetic Variant NM_001199397.3:c.3411G>A (chr4-169401824-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001199397.3(NEK1):c.3411G>A(p.Leu1137Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,160 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 10 hom. )

Consequence

NEK1
NM_001199397.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 0.0570

Publications

2 publications found

Variant links:

Genes affected

NEK1 (HGNC:7744): (NIMA related kinase 1) The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

NEK1 Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis, susceptibility to, 24
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
short-rib thoracic dysplasia 6 with or without polydactyly
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome type II
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
short rib-polydactyly syndrome, Majewski type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NEK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 4-169401824-C-T is Benign according to our data. Variant chr4-169401824-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283367.

BP7

Synonymous conserved (PhyloP=0.057 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00158 (240/152292) while in subpopulation NFE AF = 0.00245 (167/68026). AF 95% confidence interval is 0.00215. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199397.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEK1	NM_001199397.3	MANE Select	c.3411G>A	p.Leu1137Leu	synonymous	Exon 33 of 36	NP_001186326.1	Q96PY6-3
NEK1	NM_001374418.1		c.3411G>A	p.Leu1137Leu	synonymous	Exon 32 of 35	NP_001361347.1	Q96PY6-3
NEK1	NM_001374419.1		c.3327G>A	p.Leu1109Leu	synonymous	Exon 32 of 35	NP_001361348.1	Q96PY6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEK1	ENST00000507142.6	TSL:1 MANE Select	c.3411G>A	p.Leu1137Leu	synonymous	Exon 33 of 36	ENSP00000424757.2	Q96PY6-3
NEK1	ENST00000439128.6	TSL:1	c.3327G>A	p.Leu1109Leu	synonymous	Exon 31 of 34	ENSP00000408020.2	Q96PY6-1
NEK1	ENST00000511633.5	TSL:1	c.3279G>A	p.Leu1093Leu	synonymous	Exon 32 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00245

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00157

AC:

391

AN:

248476

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.000259

Gnomad AMR exome

AF:

0.000816

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00107

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00448

GnomAD4 exome

AF:

0.00194

AC:

2839

AN:

1460868

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1355

AN XY:

726686

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33460

American (AMR)

AF:

0.00101

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00345

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000267

AC:

AN:

86046

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00211

AC:

2342

AN:

1111444

Other (OTH)

AF:

0.00217

AC:

131

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

131

262

392

523

654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00158

AC:

240

AN:

152292

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41566

American (AMR)

AF:

0.00111

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00245

AC:

167

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00185

Hom.:

Bravo

AF:

0.00147

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Short-rib thoracic dysplasia 6 with or without polydactyly (2)

Connective tissue disorder (1)

NEK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.4

(source)

DANN

Benign

0.58

PhyloP100

0.057

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over