NM_002218.5:c.2575C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002218.5(ITIH4):​c.2575C>T​(p.Leu859Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48
Variant links:
Genes affected
ITIH4 (HGNC:6169): (inter-alpha-trypsin inhibitor heavy chain 4) The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

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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=0.33850837).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITIH4NM_002218.5 linkc.2575C>T p.Leu859Phe missense_variant Exon 22 of 24 ENST00000266041.9 NP_002209.2 Q14624-1B7ZKJ8B2RMS9
ITIH4NM_001166449.2 linkc.2485C>T p.Leu829Phe missense_variant Exon 20 of 22 NP_001159921.1 Q14624-3B7ZKJ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITIH4ENST00000266041.9 linkc.2575C>T p.Leu859Phe missense_variant Exon 22 of 24 1 NM_002218.5 ENSP00000266041.4 Q14624-1
ENSG00000243696ENST00000468472.1 linkn.*4211C>T non_coding_transcript_exon_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8
ENSG00000243696ENST00000468472.1 linkn.*4211C>T 3_prime_UTR_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461538
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727040
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2575C>T (p.L859F) alteration is located in exon 22 (coding exon 22) of the ITIH4 gene. This alteration results from a C to T substitution at nucleotide position 2575, causing the leucine (L) at amino acid position 859 to be replaced by a phenylalanine (F). 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
0.15
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.059
T;T;.
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.22
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.67
T;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.34
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
M;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.41
T;T;T
Sift4G
Benign
0.42
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.41
MutPred
0.59
.;Gain of glycosylation at T869 (P = 0.0374);.;
MVP
0.36
MPC
0.98
ClinPred
0.84
D
GERP RS
4.1
Varity_R
0.049
gMVP
0.25

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-52848276; API