NM_031965.2:c.23C>T

Variant names:

• chr17-3723958-C-T
• rs762347012
• NM_031965.2:c.23C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031965.2(HASPIN):​c.23C>T​(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,417,096 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P8S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HASPIN NM_031965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.122
• Publications: 1 publications found

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]

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]

P2RX5 (HGNC:8536): (purinergic receptor P2X 5) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream gene, TAX1BP3 (Tax1 binding protein 3). [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06739816).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HASPIN	NM_031965.2	MANE Select	c.23C>T	p.Pro8Leu	missense	Exon 1 of 1	NP_114171.2	A0PJ70
	ITGAE	NM_002208.5	MANE Select	c.3085-214G>A		intron	N/A	NP_002199.3
	ITGAE	NM_001425071.1		c.3007-214G>A		intron	N/A	NP_001412000.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HASPIN	ENST00000325418.5	TSL:6 MANE Select	c.23C>T	p.Pro8Leu	missense	Exon 1 of 1	ENSP00000325290.4	Q8TF76-1
	ITGAE	ENST00000263087.9	TSL:1 MANE Select	c.3085-214G>A		intron	N/A	ENSP00000263087.4	P38570
	ITGAE	ENST00000949198.1		c.3181-214G>A		intron	N/A	ENSP00000619257.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000474 AC: 1 AN: 210818 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000342

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000141 AC: 2 AN: 1417096 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700514

African (AFR) AF: 0.00 AC: 0 AN: 31490

American (AMR) AF: 0.0000256 AC: 1 AN: 38992

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24408

East Asian (EAS) AF: 0.00 AC: 0 AN: 38256

South Asian (SAS) AF: 0.00 AC: 0 AN: 83128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1089074

Other (OTH) AF: 0.00 AC: 0 AN: 58128

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000843 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.8
DANN	Benign	0.85
DEOGEN2	Benign	0.054	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.12
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.042
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.16		Loss of glycosylation at P8 (P = 0.018)
MVP		0.17
MPC		0.39
ClinPred		0.090	T
GERP RS		0.051
PromoterAI		-0.13	Neutral
Varity_R		0.039
gMVP		0.19
Mutation Taster		=98/2	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: rs762347012; hg19: chr17-3627252;