10-7709182-A-T

Variant names:

• chr10-7709182-A-T
• rs749501304
• NM_002216.3:c.353A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002216.3(ITIH2):​c.353A>T​(p.Asn118Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. N118S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITIH2 NM_002216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

Genes affected

ITIH2 (HGNC:6167): (inter-alpha-trypsin inhibitor heavy chain 2) The inter-alpha-trypsin inhibitors (ITI) are a family of structurally related plasma serine protease inhibitors involved in extracellular matrix stabilization and in prevention of tumor metastasis. The ITI family contains multiple proteins made up of a light chain (see MIM 176870) and a variable number of heavy chains (Salier et al., 1987 [PubMed 2446322]; Himmelfarb et al., 2004 [PubMed 14744536]).[supplied by OMIM, Nov 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) (complex) asparagine (size 0) in uniprot entity ITIH2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH2	NM_002216.3	c.353A>T	p.Asn118Ile	missense_variant	Exon 4 of 21	ENST00000358415.9	NP_002207.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH2	ENST00000358415.9	c.353A>T	p.Asn118Ile	missense_variant	Exon 4 of 21	1	NM_002216.3	ENSP00000351190.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;T;T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.1	M;.;.
PhyloP100		8.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.85		Loss of catalytic residue at N118 (P = 0.0124);.;.;
MVP		0.68
MPC		0.52
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.65
Mutation Taster		=25/75	disease causing

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: rs749501304; hg19: chr10-7751145;