rs184804243

Variant names:

• chr4-169537893-A-G
• rs184804243
• NM_001199397.3:c.1581T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001199397.3(NEK1):​c.1581T>C​(p.Ala527Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,604,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: NEK1 NM_001199397.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.16
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-169537893-A-G is Benign according to our data. Variant chr4-169537893-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00172 (262/152286) while in subpopulation AFR AF = 0.00592 (246/41576). AF 95% confidence interval is 0.00531. There are 1 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.1581T>C	p.Ala527Ala	synonymous	Exon 19 of 36	NP_001186326.1
	NEK1	NM_001374418.1		c.1581T>C	p.Ala527Ala	synonymous	Exon 18 of 35	NP_001361347.1
	NEK1	NM_001374419.1		c.1581T>C	p.Ala527Ala	synonymous	Exon 19 of 35	NP_001361348.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.1581T>C	p.Ala527Ala	synonymous	Exon 19 of 36	ENSP00000424757.2
	NEK1	ENST00000439128.6	TSL:1	c.1581T>C	p.Ala527Ala	synonymous	Exon 18 of 34	ENSP00000408020.2
	NEK1	ENST00000511633.5	TSL:1	c.1449T>C	p.Ala483Ala	synonymous	Exon 18 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 261 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000403 AC: 98 AN: 243470 AF XY: 0.000363

Gnomad AFR exome AF: 0.00596

Gnomad AMR exome AF: 0.0000915

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000144 AC: 209 AN: 1451898 Hom.: 0 Cov.: 30 AF XY: 0.000119 AC XY: 86 AN XY: 722016

African (AFR) AF: 0.00479 AC: 159 AN: 33196

American (AMR) AF: 0.000205 AC: 9 AN: 43976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84142

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53054

Middle Eastern (MID) AF: 0.000523 AC: 3 AN: 5738

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1106628

Other (OTH) AF: 0.000534 AC: 32 AN: 59924

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74454

African (AFR) AF: 0.00592 AC: 246 AN: 41576

American (AMR) AF: 0.000458 AC: 7 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.000658 Hom.: 0

Bravo AF: 0.00187

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Short-rib thoracic dysplasia 6 with or without polydactyly (2)
-	-	1	Connective tissue disorder (1)
-	-	1	NEK1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.2
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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: rs184804243; hg19: chr4-170459044;