Genetic Variant HASPIN:p.Arg134Leu (chr17-3724336-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031965.2(HASPIN):c.401G>T(p.Arg134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. R134P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HASPIN
NM_031965.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.472

Publications

0 publications found

Variant links:

Genes affected

HASPIN (HGNC:19682): (histone H3 associated protein kinase) Enables ATP binding activity and histone kinase activity (H3-T3 specific). Involved in histone H3-T3 phosphorylation involved in chromosome passenger complex localization to kinetochore; intracellular signal transduction; and mitotic sister chromatid cohesion. Located in centrosome; nucleoplasm; and spindle. [provided by Alliance of Genome Resources, Apr 2022]

HASPIN links:

ITGAE (HGNC:6147): (integrin subunit alpha E) Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This gene encodes an I-domain-containing alpha integrin that undergoes post-translational cleavage in the extracellular domain, yielding disulfide-linked heavy and light chains. In combination with the beta 7 integrin, this protein forms the E-cadherin binding integrin known as the human mucosal lymphocyte-1 antigen. This protein is preferentially expressed in human intestinal intraepithelial lymphocytes (IEL), and in addition to a role in adhesion, it may serve as an accessory molecule for IEL activation. [provided by RefSeq, Jul 2008]

ITGAE links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07463595).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031965.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HASPIN	NM_031965.2	MANE Select	c.401G>T	p.Arg134Leu	missense	Exon 1 of 1	NP_114171.2	A0PJ70
ITGAE	NM_002208.5	MANE Select	c.3085-592C>A		intron	N/A	NP_002199.3
ITGAE	NM_001425071.1		c.3007-592C>A		intron	N/A	NP_001412000.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HASPIN	ENST00000325418.5	TSL:6 MANE Select	c.401G>T	p.Arg134Leu	missense	Exon 1 of 1	ENSP00000325290.4	Q8TF76-1
ITGAE	ENST00000263087.9	TSL:1 MANE Select	c.3085-592C>A		intron	N/A	ENSP00000263087.4	P38570
ITGAE	ENST00000949198.1		c.3181-592C>A		intron	N/A	ENSP00000619257.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439530

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715678

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33004

American (AMR)

AF:

0.00

AC:

AN:

42870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

38662

South Asian (SAS)

AF:

0.00

AC:

AN:

84702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42902

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106142

Other (OTH)

AF:

0.00

AC:

AN:

59672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.072

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.56

M_CAP

Benign

0.013

MetaRNN

Benign

0.075

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

0.47

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

REVEL

Benign

0.026

Sift

Uncertain

0.0050

Sift4G

Benign

0.092

Polyphen

0.013

Vest4

0.12

MutPred

0.38

Gain of catalytic residue at R134 (P = 0.1544)

MVP

0.28

MPC

0.72

ClinPred

0.23

GERP RS

2.2

PromoterAI

0.097

Neutral

(source)

Varity_R

0.17

gMVP

0.15

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over