chr10-7566039-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_030569.7(ITIH5):c.2518G>A(p.Gly840Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,536 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 0.000013 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
ITIH5
NM_030569.7 missense
NM_030569.7 missense
Scores
6
7
2
Clinical Significance
Conservation
PhyloP100: 7.43
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITIH5 | NM_030569.7 | c.2518G>A | p.Gly840Arg | missense_variant | 13/14 | ENST00000397146.7 | |
ITIH5 | NM_032817.6 | c.1876G>A | p.Gly626Arg | missense_variant | 9/10 | ||
ITIH5 | XM_011519713.4 | c.2593G>A | p.Gly865Arg | missense_variant | 14/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITIH5 | ENST00000397146.7 | c.2518G>A | p.Gly840Arg | missense_variant | 13/14 | 1 | NM_030569.7 | P1 | |
ITIH5 | ENST00000613909.4 | c.1876G>A | p.Gly626Arg | missense_variant | 9/10 | 1 | |||
ITIH5 | ENST00000473591.1 | n.780G>A | non_coding_transcript_exon_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251166Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135736
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461386Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 726984
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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 01, 2021 | The c.2518G>A (p.G840R) alteration is located in exon 13 (coding exon 13) of the ITIH5 gene. This alteration results from a G to A substitution at nucleotide position 2518, causing the glycine (G) at amino acid position 840 to be replaced by an arginine (R). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D
Vest4
MutPred
Gain of helix (P = 0.062);.;
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