4-169394356-C-T

Variant names:

• chr4-169394356-C-T
• rs139328912
• NM_001199397.3:c.*154G>A

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.*154G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 524,736 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (141 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (116 hom.)
• Consequence: NEK1 NM_001199397.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.173
• Publications: 1 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-169394356-C-T is Benign according to our data. Variant chr4-169394356-C-T is described in ClinVar as Benign. ClinVar VariationId is 348087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.115 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.*154G>A		3_prime_UTR	Exon 36 of 36	NP_001186326.1	Q96PY6-3
	NEK1	NM_001374418.1		c.*154G>A		3_prime_UTR	Exon 35 of 35	NP_001361347.1	Q96PY6-3
	NEK1	NM_001374419.1		c.*154G>A		3_prime_UTR	Exon 35 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.*154G>A		3_prime_UTR	Exon 36 of 36	ENSP00000424757.2	Q96PY6-3
	NEK1	ENST00000439128.6	TSL:1	c.*154G>A		3_prime_UTR	Exon 34 of 34	ENSP00000408020.2	Q96PY6-1
	NEK1	ENST00000511633.5	TSL:1	c.*154G>A		3_prime_UTR	Exon 35 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2076 AN: 152104 Hom.: 137 Cov.: 33

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.00543 AC: 2021 AN: 372514 Hom.: 116 Cov.: 5 AF XY: 0.00488 AC XY: 962 AN XY: 196938

African (AFR) AF: 0.00196 AC: 16 AN: 8144

American (AMR) AF: 0.139 AC: 1334 AN: 9604

Ashkenazi Jewish (ASJ) AF: 0.0000770 AC: 1 AN: 12980

East Asian (EAS) AF: 0.0000423 AC: 1 AN: 23618

South Asian (SAS) AF: 0.000880 AC: 28 AN: 31802

European-Finnish (FIN) AF: 0.000682 AC: 26 AN: 38148

Middle Eastern (MID) AF: 0.000668 AC: 2 AN: 2994

European-Non Finnish (NFE) AF: 0.00194 AC: 435 AN: 223820

Other (OTH) AF: 0.00832 AC: 178 AN: 21404

GnomAD4 genome AF: 0.0137 AC: 2092 AN: 152222 Hom.: 141 Cov.: 33 AF XY: 0.0150 AC XY: 1119 AN XY: 74440

African (AFR) AF: 0.00221 AC: 92 AN: 41544

American (AMR) AF: 0.120 AC: 1832 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00190 AC: 129 AN: 67972

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00842 Hom.: 9

Bravo AF: 0.0229

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Short-rib thoracic dysplasia 6 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.83
DANN	Benign	0.38
PhyloP100		-0.17
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: rs139328912; hg19: chr4-170315507;