chr10-7566394-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_030569.7(ITIH5):c.2163C>G(p.Asn721Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,597,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
ITIH5
NM_030569.7 missense
NM_030569.7 missense
Scores
2
5
8
Clinical Significance
Conservation
PhyloP100: 0.0780
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.895
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITIH5 | NM_030569.7 | c.2163C>G | p.Asn721Lys | missense_variant | 13/14 | ENST00000397146.7 | |
ITIH5 | NM_032817.6 | c.1521C>G | p.Asn507Lys | missense_variant | 9/10 | ||
ITIH5 | XM_011519713.4 | c.2238C>G | p.Asn746Lys | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITIH5 | ENST00000397146.7 | c.2163C>G | p.Asn721Lys | missense_variant | 13/14 | 1 | NM_030569.7 | P1 | |
ITIH5 | ENST00000613909.4 | c.1521C>G | p.Asn507Lys | missense_variant | 9/10 | 1 | |||
ITIH5 | ENST00000473591.1 | n.425C>G | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152002Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247396Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133470
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GnomAD4 exome AF: 0.00000346 AC: 5AN: 1445638Hom.: 0 Cov.: 31 AF XY: 0.00000559 AC XY: 4AN XY: 715596
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The c.2163C>G (p.N721K) alteration is located in exon 13 (coding exon 13) of the ITIH5 gene. This alteration results from a C to G substitution at nucleotide position 2163, causing the asparagine (N) at amino acid position 721 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D
Vest4
MutPred
Gain of ubiquitination at N721 (P = 0.0162);.;
MVP
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at