Variant 2-233837643-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_018410.5(HJURP):c.2181C>G(p.Asn727Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,600,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

HJURP
NM_018410.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00600

Variant links:

Genes affected

HJURP (HGNC:25444): (Holliday junction recognition protein) Enables histone binding activity and identical protein binding activity. Involved in several processes, including CENP-A containing chromatin assembly; regulation of DNA binding activity; and regulation of protein-containing complex assembly. Located in kinetochore; mitochondrion; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

HJURP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043718755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HJURP	NM_018410.5 linkuse as main transcript	c.2181C>G	p.Asn727Lys	missense_variant	9/9	ENST00000411486.7	NP_060880.3	Q8NCD3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HJURP	ENST00000411486.7 linkuse as main transcript	c.2181C>G	p.Asn727Lys	missense_variant	9/9	1	NM_018410.5	ENSP00000414109.1	Q8NCD3-1
HJURP	ENST00000433484.2 linkuse as main transcript	n.138C>G		non_coding_transcript_exon_variant	2/3	5		ENSP00000395207.1	H7C0I6
HJURP	ENST00000432087.5 linkuse as main transcript	c.2019C>G	p.Asn673Lys	missense_variant	7/7	2		ENSP00000407208.1	Q8NCD3-2
HJURP	ENST00000441687.5 linkuse as main transcript	c.1926C>G	p.Asn642Lys	missense_variant	6/6	2		ENSP00000401944.1	Q8NCD3-3

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151750

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

243844

Hom.:

AF XY:

0.00000758

AC XY:

AN XY:

131902

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1449210

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721290

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151750

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74046

show subpopulations

Gnomad4 AFR

AF:

0.0000727

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.2181C>G (p.N727K) alteration is located in exon 9 (coding exon 9) of the HJURP gene. This alteration results from a C to G substitution at nucleotide position 2181, causing the asparagine (N) at amino acid position 727 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.75

DANN

Benign

0.58

DEOGEN2

Benign

0.0025

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.35

T;T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.81

.;.;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.48

N;N;N

REVEL

Benign

0.045

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.070

T;T;T

Polyphen

0.041

B;B;B

Vest4

0.080

MutPred

0.19

.;.;Gain of ubiquitination at N727 (P = 9e-04);

MVP

0.040

MPC

0.082

ClinPred

0.033

GERP RS

-2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.023

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over