NEK1 p.Ala463Val

Variant names:

• chr4-169555974-G-A
• rs34540355
• NM_001199397.3:c.1388C>T
• NEK1 p.Ala463Val

Your query was ambiguous. Multiple possible variants found:

• chr4-169555974-G-A
• chr4-169555973-AG-GA
• chr4-169555973-AG-TA
• chr4-169555973-AG-CA

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001199397.3(NEK1):​c.1388C>T​(p.Ala463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,538 control chromosomes in the GnomAD database, including 2,679 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A463T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (152 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2527 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.55
• Publications: 16 publications found

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• short-rib thoracic dysplasia 6 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• orofaciodigital syndrome type II

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016297698).
• BP6: Variant 4-169555974-G-A is Benign according to our data. Variant chr4-169555974-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.1388C>T	p.Ala463Val	missense	Exon 17 of 36	NP_001186326.1	Q96PY6-3
	NEK1	NM_001374418.1		c.1388C>T	p.Ala463Val	missense	Exon 16 of 35	NP_001361347.1	Q96PY6-3
	NEK1	NM_001374419.1		c.1388C>T	p.Ala463Val	missense	Exon 17 of 35	NP_001361348.1	Q96PY6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.1388C>T	p.Ala463Val	missense	Exon 17 of 36	ENSP00000424757.2	Q96PY6-3
	NEK1	ENST00000439128.6	TSL:1	c.1388C>T	p.Ala463Val	missense	Exon 16 of 34	ENSP00000408020.2	Q96PY6-1
	NEK1	ENST00000511633.5	TSL:1	c.1388C>T	p.Ala463Val	missense	Exon 17 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5471 AN: 152020 Hom.: 152 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0407

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0578

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0358 AC: 8903 AN: 248794 AF XY: 0.0366

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.0224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0581

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0546 AC: 79763 AN: 1461400 Hom.: 2527 Cov.: 32 AF XY: 0.0536 AC XY: 38991 AN XY: 726974

African (AFR) AF: 0.00983 AC: 329 AN: 33472

American (AMR) AF: 0.0251 AC: 1122 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 543 AN: 26122

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39680

South Asian (SAS) AF: 0.0164 AC: 1417 AN: 86208

European-Finnish (FIN) AF: 0.0204 AC: 1091 AN: 53398

Middle Eastern (MID) AF: 0.0298 AC: 172 AN: 5768

European-Non Finnish (NFE) AF: 0.0650 AC: 72206 AN: 1111714

Other (OTH) AF: 0.0477 AC: 2880 AN: 60362

GnomAD4 genome AF: 0.0360 AC: 5473 AN: 152138 Hom.: 152 Cov.: 32 AF XY: 0.0337 AC XY: 2506 AN XY: 74384

African (AFR) AF: 0.0102 AC: 425 AN: 41532

American (AMR) AF: 0.0406 AC: 620 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4812

European-Finnish (FIN) AF: 0.0198 AC: 210 AN: 10580

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.0578 AC: 3928 AN: 67990

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0513 Hom.: 815

Bravo AF: 0.0372

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Short-rib thoracic dysplasia 6 with or without polydactyly (4)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.091
Sift	Benign	0.24	T
Sift4G	Benign	0.10	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.16
Mutation Taster		=97/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34540355;

hg19: chr4-170477125;