Variant 3-52813968-A-G 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.2723+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,609,854 control chromosomes in the GnomAD database, including 2,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.070 ( 1154 hom., cov: 32)

Exomes 𝑓: 0.019 ( 1674 hom. )

Consequence

ITIH4
NM_002218.5 splice_region, intron

Scores

Splicing: ADA: 0.00001467

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.581

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 3-52813968-A-G is Benign according to our data. Variant chr3-52813968-A-G is described in ClinVar as [Benign]. Clinvar id is 3060455.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.214 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.2723+7T>C		splice_region_variant, intron_variant		ENST00000266041.9	NP_002209.2
ITIH4	NM_001166449.2 linkuse as main transcript	c.2633+7T>C		splice_region_variant, intron_variant			NP_001159921.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITIH4	ENST00000266041.9 linkuse as main transcript	c.2723+7T>C		splice_region_variant, intron_variant		1	NM_002218.5	ENSP00000266041	P2	Q14624-1

Frequencies

GnomAD3 genomes

AF:

0.0702

AC:

10681

AN:

152062

Hom.:

1152

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0263

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0119

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00653

Gnomad OTH

AF:

0.0464

GnomAD3 exomes

AF:

0.0355

AC:

8772

AN:

246802

Hom.:

677

AF XY:

0.0373

AC XY:

4987

AN XY:

133782

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.00171

Gnomad EAS exome

AF:

0.0137

Gnomad SAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.00605

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0190

AC:

27628

AN:

1457674

Hom.:

1674

Cov.:

AF XY:

0.0214

AC XY:

15520

AN XY:

725078

show subpopulations

Gnomad4 AFR exome

AF:

0.228

Gnomad4 AMR exome

AF:

0.0140

Gnomad4 ASJ exome

AF:

0.00161

Gnomad4 EAS exome

AF:

0.00928

Gnomad4 SAS exome

AF:

0.118

Gnomad4 FIN exome

AF:

0.00226

Gnomad4 NFE exome

AF:

0.00629

Gnomad4 OTH exome

AF:

0.0270

GnomAD4 genome

AF:

0.0703

AC:

10702

AN:

152180

Hom.:

1154

Cov.:

AF XY:

0.0710

AC XY:

5283

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.218

Gnomad4 AMR

AF:

0.0263

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.0122

Gnomad4 SAS

AF:

0.125

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00651

Gnomad4 OTH

AF:

0.0459

Alfa

AF:

0.0204

Hom.:

369

Bravo

AF:

0.0765

Asia WGS

AF:

0.0720

AC:

250

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

Nov 06, 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

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.95

DANN

Benign

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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