rs748153261

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002218.5(ITIH4):​c.2584C>T​(p.Arg862Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.231
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]

Genome browser will be placed here

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 rank MANE Protein UniProt
ITIH4NM_002218.5 linkc.2584C>T p.Arg862Cys missense_variant Exon 22 of 24 ENST00000266041.9 NP_002209.2 Q14624-1B7ZKJ8B2RMS9
ITIH4NM_001166449.2 linkc.2494C>T p.Arg832Cys 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.2584C>T p.Arg862Cys missense_variant Exon 22 of 24 1 NM_002218.5 ENSP00000266041.4 Q14624-1
ENSG00000243696ENST00000468472.1 linkn.*4220C>T non_coding_transcript_exon_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8
ENSG00000243696ENST00000468472.1 linkn.*4220C>T 3_prime_UTR_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249860
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135114
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461360
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
726946
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.21
T;T;.
Eigen
Benign
-0.098
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.028
N
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.017
T
MetaRNN
Uncertain
0.61
D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.2
M;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-2.4
N;N;N
REVEL
Benign
0.12
Sift
Benign
0.20
T;T;T
Sift4G
Uncertain
0.054
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.52
MutPred
0.66
.;Loss of disorder (P = 0.0281);.;
MVP
0.52
MPC
1.1
ClinPred
0.78
D
GERP RS
1.6
Varity_R
0.095
gMVP
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748153261; hg19: chr3-52848267; API