10-7566178-G-T

Variant summary

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

The NM_030569.7(ITIH5):c.2379C>A(p.Asn793Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ITIH5 NM_030569.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.52

Genes affected

ITIH5 (HGNC:21449): (inter-alpha-trypsin inhibitor heavy chain 5) This gene encodes a heavy chain component of one of the inter-alpha-trypsin inhibitor (ITI) family members. ITI proteins are involved in extracellular matrix stabilization and in the prevention of tumor metastasis. They are also structurally related plasma serine protease inhibitors and are composed of a light chain and varying numbers of heavy chains. This family member is thought to function as a tumor suppressor in breast and thyroid cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

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=0.08410263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH5	NM_030569.7	c.2379C>A	p.Asn793Lys	missense_variant	13/14	ENST00000397146.7
ITIH5	NM_032817.6	c.1737C>A	p.Asn579Lys	missense_variant	9/10
ITIH5	XM_011519713.4	c.2454C>A	p.Asn818Lys	missense_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH5	ENST00000397146.7	c.2379C>A	p.Asn793Lys	missense_variant	13/14	1	NM_030569.7	P1
ITIH5	ENST00000613909.4	c.1737C>A	p.Asn579Lys	missense_variant	9/10	1
ITIH5	ENST00000473591.1	n.641C>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251264 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Jun 03, 2022

The c.2379C>A (p.N793K) alteration is located in exon 13 (coding exon 13) of the ITIH5 gene. This alteration results from a C to A substitution at nucleotide position 2379, causing the asparagine (N) at amino acid position 793 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.0010
Dann	Benign	0.86
DEOGEN2	Benign	0.0022	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.37	T;T
Vest4		0.34
MutPred		0.41		Gain of ubiquitination at N793 (P = 0.0267);.;
MVP		0.17
ClinPred		0.30	T
GERP RS		-12
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs142836742; hg19: chr10-7608141;