Variant 3-52818044-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002218.5(ITIH4):c.2296+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 1,603,458 control chromosomes in the GnomAD database, including 137,055 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 (★).

Frequency

Genomes: 𝑓 0.48 ( 18714 hom., cov: 33)

Exomes 𝑓: 0.40 ( 118341 hom. )

Consequence

ITIH4
NM_002218.5 splice_region, intron

Scores

Splicing: ADA: 0.00008111

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.423

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 -14 ACMG points.

BP4

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

BP6

Variant 3-52818044-T-C is Benign according to our data. Variant chr3-52818044-T-C is described in ClinVar as [Benign]. Clinvar id is 3059539.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITIH4	NM_002218.5 linkuse as main transcript	c.2296+8A>G		splice_region_variant, intron_variant		ENST00000266041.9
ITIH4	NM_001166449.2 linkuse as main transcript	c.2206+8A>G		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITIH4	ENST00000266041.9 linkuse as main transcript	c.2296+8A>G		splice_region_variant, intron_variant		1	NM_002218.5	P2	Q14624-1

Frequencies

GnomAD3 genomes

AF:

0.480

AC:

72905

AN:

152042

Hom.:

18691

Cov.:

show subpopulations

Gnomad AFR

AF:

0.663

Gnomad AMI

AF:

0.534

Gnomad AMR

AF:

0.546

Gnomad ASJ

AF:

0.443

Gnomad EAS

AF:

0.382

Gnomad SAS

AF:

0.399

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.388

Gnomad OTH

AF:

0.451

GnomAD3 exomes

AF:

0.433

AC:

108428

AN:

250506

Hom.:

24811

AF XY:

0.422

AC XY:

57277

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.669

Gnomad AMR exome

AF:

0.587

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.361

Gnomad SAS exome

AF:

0.399

Gnomad FIN exome

AF:

0.370

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

AF:

0.399

AC:

578556

AN:

1451298

Hom.:

118341

Cov.:

AF XY:

0.397

AC XY:

287095

AN XY:

722526

show subpopulations

Gnomad4 AFR exome

AF:

0.674

Gnomad4 AMR exome

AF:

0.579

Gnomad4 ASJ exome

AF:

0.438

Gnomad4 EAS exome

AF:

0.407

Gnomad4 SAS exome

AF:

0.390

Gnomad4 FIN exome

AF:

0.364

Gnomad4 NFE exome

AF:

0.384

Gnomad4 OTH exome

AF:

0.402

GnomAD4 genome

AF:

0.480

AC:

72980

AN:

152160

Hom.:

18714

Cov.:

AF XY:

0.478

AC XY:

35517

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.663

Gnomad4 AMR

AF:

0.545

Gnomad4 ASJ

AF:

0.443

Gnomad4 EAS

AF:

0.381

Gnomad4 SAS

AF:

0.398

Gnomad4 FIN

AF:

0.354

Gnomad4 NFE

AF:

0.388

Gnomad4 OTH

AF:

0.453

Alfa

AF:

0.415

Hom.:

8058

Bravo

AF:

0.503

Asia WGS

AF:

0.446

AC:

1550

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

ITIH4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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

1.3

Dann

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000081

dbscSNV1_RF

Benign

0.0020

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.

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