dbSNP rs2276817: ITIH4:p.Val130Val (chr3-52826920-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_002218.5(ITIH4):c.390G>A(p.Val130Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,613,872 control chromosomes in the GnomAD database, including 47,475 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.25 ( 4842 hom., cov: 32)

Exomes 𝑓: 0.23 ( 42633 hom. )

Consequence

ITIH4
NM_002218.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0210

Publications

48 publications found

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 was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 3-52826920-C-T is Benign according to our data. Variant chr3-52826920-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060681.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.021 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH4	NM_002218.5 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 4 of 24	ENST00000266041.9	NP_002209.2	Q14624-1B7ZKJ8B2RMS9
ITIH4	NM_001166449.2 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 4 of 22		NP_001159921.1	Q14624-3B7ZKJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITIH4	ENST00000266041.9 link	c.390G>A	p.Val130Val	synonymous_variant	Exon 4 of 24	1	NM_002218.5	ENSP00000266041.4	Q14624-1
ENSG00000243696	ENST00000468472.1 link	n.*522G>A		non_coding_transcript_exon_variant	Exon 9 of 24	2		ENSP00000422253.1	D6R8Y8
ENSG00000243696	ENST00000468472.1 link	n.*522G>A		3_prime_UTR_variant	Exon 9 of 24	2		ENSP00000422253.1	D6R8Y8

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37278

AN:

151960

Hom.:

4841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.208

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.320

Gnomad SAS

AF:

0.129

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.234

Gnomad OTH

AF:

0.243

GnomAD2 exomes

AF:

0.262

AC:

65839

AN:

251380

AF XY:

0.248

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.473

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.309

Gnomad FIN exome

AF:

0.266

Gnomad NFE exome

AF:

0.231

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.234

AC:

342172

AN:

1461794

Hom.:

42633

Cov.:

AF XY:

0.230

AC XY:

167258

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.201

AC:

6728

AN:

33478

American (AMR)

AF:

0.458

AC:

20485

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

8401

AN:

26134

East Asian (EAS)

AF:

0.348

AC:

13833

AN:

39700

South Asian (SAS)

AF:

0.119

AC:

10251

AN:

86256

European-Finnish (FIN)

AF:

0.256

AC:

13650

AN:

53360

Middle Eastern (MID)

AF:

0.224

AC:

1290

AN:

5768

European-Non Finnish (NFE)

AF:

0.228

AC:

253843

AN:

1111986

Other (OTH)

AF:

0.227

AC:

13691

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

15793

31586

47379

63172

78965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8770

17540

26310

35080

43850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.245

AC:

37299

AN:

152078

Hom.:

4842

Cov.:

AF XY:

0.247

AC XY:

18362

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.208

AC:

8634

AN:

41502

American (AMR)

AF:

0.374

AC:

5721

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

1084

AN:

3466

East Asian (EAS)

AF:

0.320

AC:

1652

AN:

5158

South Asian (SAS)

AF:

0.129

AC:

619

AN:

4810

European-Finnish (FIN)

AF:

0.258

AC:

2727

AN:

10588

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.234

AC:

15909

AN:

67948

Other (OTH)

AF:

0.246

AC:

518

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1434

2868

4303

5737

7171

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.246

Hom.:

8273

Bravo

AF:

0.256

Asia WGS

AF:

0.237

AC:

822

AN:

3478

EpiCase

AF:

0.237

EpiControl

AF:

0.230

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

ITIH4-related disorder

Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

-0.51

CADD

Benign

7.2

(source)

DANN

Benign

0.88

PhyloP100

-0.021

PromoterAI

0.016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over