10-7569734-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_030569.7(ITIH5):c.2083G>A(p.Val695Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )
Consequence
ITIH5
NM_030569.7 missense
NM_030569.7 missense
Scores
8
7
Clinical Significance
Conservation
PhyloP100: 3.60
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2684437).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITIH5 | NM_030569.7 | c.2083G>A | p.Val695Met | missense_variant | 12/14 | ENST00000397146.7 | |
ITIH5 | NM_032817.6 | c.1441G>A | p.Val481Met | missense_variant | 8/10 | ||
ITIH5 | XM_011519713.4 | c.2158G>A | p.Val720Met | missense_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITIH5 | ENST00000397146.7 | c.2083G>A | p.Val695Met | missense_variant | 12/14 | 1 | NM_030569.7 | P1 | |
ITIH5 | ENST00000613909.4 | c.1441G>A | p.Val481Met | missense_variant | 8/10 | 1 | |||
ITIH5 | ENST00000473591.1 | n.345G>A | non_coding_transcript_exon_variant | 2/3 | 3 | ||||
ITIH5 | ENST00000492668.5 | n.250G>A | non_coding_transcript_exon_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249866Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135076
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GnomAD4 exome AF: 0.0000260 AC: 38AN: 1460512Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 726534
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152318Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74484
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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 | Mar 13, 2023 | The c.2083G>A (p.V695M) alteration is located in exon 12 (coding exon 12) of the ITIH5 gene. This alteration results from a G to A substitution at nucleotide position 2083, causing the valine (V) at amino acid position 695 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Uncertain
T;T
Vest4
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