10-7563162-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_030569.7(ITIH5):c.2750G>C(p.Gly917Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
ITIH5
NM_030569.7 missense
NM_030569.7 missense
Scores
3
8
4
Clinical Significance
Conservation
PhyloP100: 7.46
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITIH5 | NM_030569.7 | c.2750G>C | p.Gly917Ala | missense_variant | 14/14 | ENST00000397146.7 | |
ITIH5 | NM_032817.6 | c.2108G>C | p.Gly703Ala | missense_variant | 10/10 | ||
ITIH5 | XM_011519713.4 | c.2825G>C | p.Gly942Ala | missense_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITIH5 | ENST00000397146.7 | c.2750G>C | p.Gly917Ala | missense_variant | 14/14 | 1 | NM_030569.7 | P1 | |
ITIH5 | ENST00000613909.4 | c.2108G>C | p.Gly703Ala | missense_variant | 10/10 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152206Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000954 AC: 24AN: 251496Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135922
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GnomAD4 exome AF: 0.000144 AC: 210AN: 1461832Hom.: 1 Cov.: 35 AF XY: 0.000136 AC XY: 99AN XY: 727226
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GnomAD4 genome ? AF: 0.0000656 AC: 10AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74490
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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 | Feb 28, 2023 | The c.2750G>C (p.G917A) alteration is located in exon 14 (coding exon 14) of the ITIH5 gene. This alteration results from a G to C substitution at nucleotide position 2750, causing the glycine (G) at amino acid position 917 to be replaced by an alanine (A). 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
Uncertain
T
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
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Sift4G
Pathogenic
D;D
Vest4
MutPred
Gain of ubiquitination at K920 (P = 0.0898);.;
MVP
ClinPred
T
GERP RS
gMVP
Splicing
Name
Calibrated prediction
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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