17-3724442-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031965.2(HASPIN):c.507C>G(p.Phe169Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HASPIN NM_031965.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.861

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08343691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HASPIN	NM_031965.2	c.507C>G	p.Phe169Leu	missense_variant	1/1	ENST00000325418.5
ITGAE	NM_002208.5	c.3085-698G>C		intron_variant		ENST00000263087.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HASPIN	ENST00000325418.5	c.507C>G	p.Phe169Leu	missense_variant	1/1		NM_031965.2	P1
ITGAE	ENST00000263087.9	c.3085-698G>C		intron_variant		1	NM_002208.5	P1
ITGAE	ENST00000571185.1	n.880G>C		non_coding_transcript_exon_variant	7/7	3
ITGAE	ENST00000570415.5	n.479-698G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.507C>G (p.F169L) alteration is located in exon 1 (coding exon 1) of the GSG2 gene. This alteration results from a C to G substitution at nucleotide position 507, causing the phenylalanine (F) at amino acid position 169 to be replaced by a leucine (L). 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.048
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.31	T
Polyphen		0.0020	B
Vest4		0.14
MutPred		0.36		Loss of sheet (P = 0.0142);
MVP		0.23
MPC		0.46
ClinPred		0.64	D
GERP RS		3.7
Varity_R		0.42
gMVP		0.11

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-3627736;