Variant chr3-52818522-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_002218.5(ITIH4):c.2092C>A(p.Pro698Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,601,242 control chromosomes in the GnomAD database, including 58,684 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.27 ( 5851 hom., cov: 32)

Exomes 𝑓: 0.26 ( 52833 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.330

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:

ENSG00000243696 (HGNC:):

ENSG00000243696 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.5569072E-4).

BP6

Variant 3-52818522-G-T is Benign according to our data. Variant chr3-52818522-G-T is described in ClinVar as [Benign]. Clinvar id is 3059528.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITIH4	NM_002218.5 linkuse as main transcript	c.2092C>A	p.Pro698Thr	missense_variant	18/24	ENST00000266041.9	NP_002209.2	Q14624-1B7ZKJ8B2RMS9
ITIH4	NM_001166449.2 linkuse as main transcript	c.2002C>A	p.Pro668Thr	missense_variant	16/22		NP_001159921.1	Q14624-3B7ZKJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ITIH4	ENST00000266041.9 linkuse as main transcript	c.2092C>A	p.Pro698Thr	missense_variant	18/24	1	NM_002218.5	ENSP00000266041.4	Q14624-1
ENSG00000243696	ENST00000468472.1 linkuse as main transcript	n.*3462C>A		non_coding_transcript_exon_variant	20/24	2		ENSP00000422253.1	D6R8Y8
ENSG00000243696	ENST00000468472.1 linkuse as main transcript	n.*3462C>A		3_prime_UTR_variant	20/24	2		ENSP00000422253.1	D6R8Y8

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40896

AN:

151830

Hom.:

5854

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.402

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.318

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.272

Gnomad OTH

AF:

0.275

GnomAD3 exomes

AF:

0.281

AC:

64561

AN:

229774

Hom.:

10104

AF XY:

0.267

AC XY:

33212

AN XY:

124372

show subpopulations

Gnomad AFR exome

AF:

0.209

Gnomad AMR exome

AF:

0.488

Gnomad ASJ exome

AF:

0.329

Gnomad EAS exome

AF:

0.300

Gnomad SAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.286

Gnomad NFE exome

AF:

0.260

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.264

AC:

382228

AN:

1449294

Hom.:

52833

Cov.:

AF XY:

0.259

AC XY:

186570

AN XY:

719900

show subpopulations

Gnomad4 AFR exome

AF:

0.205

Gnomad4 AMR exome

AF:

0.473

Gnomad4 ASJ exome

AF:

0.335

Gnomad4 EAS exome

AF:

0.346

Gnomad4 SAS exome

AF:

0.129

Gnomad4 FIN exome

AF:

0.278

Gnomad4 NFE exome

AF:

0.263

Gnomad4 OTH exome

AF:

0.255

GnomAD4 genome

AF:

0.269

AC:

40909

AN:

151948

Hom.:

5851

Cov.:

AF XY:

0.270

AC XY:

20052

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.402

Gnomad4 ASJ

AF:

0.328

Gnomad4 EAS

AF:

0.317

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.272

Gnomad4 OTH

AF:

0.277

Alfa

AF:

0.265

Hom.:

10564

Bravo

AF:

0.279

TwinsUK

AF:

0.248

AC:

918

ALSPAC

AF:

0.260

AC:

1002

ESP6500AA

AF:

0.219

AC:

965

ESP6500EA

AF:

0.266

AC:

2288

ExAC

AF:

0.255

AC:

30789

Asia WGS

AF:

0.245

AC:

848

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ITIH4-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.41

DANN

Benign

0.74

DEOGEN2

Benign

0.38

T;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.35

T;T;T

MetaRNN

Benign

0.00036

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

L;.;.

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.098

Sift

Uncertain

0.017

D;D;T

Sift4G

Benign

0.15

T;T;D

Polyphen

0.011

B;B;.

Vest4

0.052

MPC

0.31

ClinPred

0.012

GERP RS

1.6

Varity_R

0.094

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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