Variant 3-52814278-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002218.5(ITIH4):c.2557C>T(p.Arg853Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,968 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.12

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]

ITIH4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16827044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5 linkuse as main transcript	c.2557C>T	p.Arg853Cys	missense_variant	22/24	ENST00000266041.9
ITIH4	NM_001166449.2 linkuse as main transcript	c.2467C>T	p.Arg823Cys	missense_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9 linkuse as main transcript	c.2557C>T	p.Arg853Cys	missense_variant	22/24	1	NM_002218.5	P2	Q14624-1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000441

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

250940

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000868

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:

0.000164

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000946

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Oct 03, 2022

The c.2557C>T (p.R853C) 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 2557, causing the arginine (R) at amino acid position 853 to be replaced by a cysteine (C). 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

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.48

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;.

Eigen

Benign

-0.020

Eigen_PC

Benign

-0.021

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.025

D;D;D

Polyphen

0.97

D;D;.

Vest4

0.35

MVP

0.52

MPC

0.95

ClinPred

0.22

GERP RS

4.1

Varity_R

0.10

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over