chr2-233840611-C-A

Position:

chr2-233840611-C-A

Variant summary

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

The NM_018410.5(HJURP):c.2169G>T(p.Glu723Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,579,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E723G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

HJURP
NM_018410.5 missense, splice_region

Scores

Splicing: ADA: 0.0009087

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.51

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:

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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=0.0324336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HJURP	NM_018410.5 linkuse as main transcript	c.2169G>T	p.Glu723Asp	missense_variant, splice_region_variant	8/9	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.2169G>T	p.Glu723Asp	missense_variant, splice_region_variant	8/9	1	NM_018410.5	ENSP00000414109.1	Q8NCD3-1
HJURP	ENST00000433484.2 linkuse as main transcript	n.126G>T		splice_region_variant, non_coding_transcript_exon_variant	1/3	5		ENSP00000395207.1	H7C0I6
HJURP	ENST00000432087.5 linkuse as main transcript	c.2007G>T	p.Glu669Asp	missense_variant, splice_region_variant	6/7	2		ENSP00000407208.1	Q8NCD3-2
HJURP	ENST00000441687.5 linkuse as main transcript	c.1914G>T	p.Glu638Asp	missense_variant, splice_region_variant	5/6	2		ENSP00000401944.1	Q8NCD3-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

220864

Hom.:

AF XY:

0.0000418

AC XY:

AN XY:

119486

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000672

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1427266

Hom.:

Cov.:

AF XY:

0.0000353

AC XY:

AN XY:

708486

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

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:

0.0000318

Gnomad4 OTH exome

AF:

0.0000680

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000313

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000494

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

Nov 12, 2024

The c.2169G>T (p.E723D) alteration is located in exon 8 (coding exon 8) of the HJURP gene. This alteration results from a G to T substitution at nucleotide position 2169, causing the glutamic acid (E) at amino acid position 723 to be replaced by an aspartic acid (D). 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

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.7

DANN

Benign

0.96

DEOGEN2

Benign

0.0056

.;.;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.33

T;T;T

M_CAP

Benign

0.0019

MetaRNN

Benign

0.032

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

.;.;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.35

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.70

P;P;P

Vest4

0.096

MutPred

0.026

.;.;Loss of helix (P = 0.079);

MVP

0.19

MPC

0.067

ClinPred

0.041

GERP RS

0.29

Varity_R

0.10

gMVP

0.032

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00091

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.060

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