rs187101592

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002218.5(ITIH4):ā€‹c.2525A>Gā€‹(p.Lys842Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…).

Frequency

Genomes: š‘“ 0.00022 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0860
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 Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03057751).
BP6
Variant 3-52814310-T-C is Benign according to our data. Variant chr3-52814310-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3286913.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITIH4NM_002218.5 linkc.2525A>G p.Lys842Arg missense_variant Exon 22 of 24 ENST00000266041.9 NP_002209.2 Q14624-1B7ZKJ8B2RMS9
ITIH4NM_001166449.2 linkc.2435A>G p.Lys812Arg 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.2525A>G p.Lys842Arg missense_variant Exon 22 of 24 1 NM_002218.5 ENSP00000266041.4 Q14624-1
ENSG00000243696ENST00000468472.1 linkn.*4161A>G non_coding_transcript_exon_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8
ENSG00000243696ENST00000468472.1 linkn.*4161A>G 3_prime_UTR_variant Exon 22 of 24 2 ENSP00000422253.1 D6R8Y8

Frequencies

GnomAD3 genomes
AF:
0.000217
AC:
33
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000796
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251366
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.000923
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461786
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.000217
AC:
33
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000228
AC XY:
17
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.000794
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000296
Hom.:
0
Bravo
AF:
0.000215
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Apr 08, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.66
CADD
Benign
13
DANN
Benign
0.96
DEOGEN2
Benign
0.075
T;T;.
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.35
N
LIST_S2
Benign
0.65
T;T;T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.031
T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.91
L;.;.
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.99
N;N;N
REVEL
Benign
0.028
Sift
Benign
0.60
T;T;T
Sift4G
Benign
0.47
T;T;T
Polyphen
0.0020
B;B;.
Vest4
0.14
MVP
0.38
MPC
0.24
ClinPred
0.021
T
GERP RS
2.5
Varity_R
0.047
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs187101592; hg19: chr3-52848326; API