rs151083454

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002218.5(ITIH4):c.2677G>A(p.Gly893Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,613,802 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0059 ( 59 hom. )

Consequence

ITIH4
NM_002218.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.239

Publications

11 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028267205).

BP6

Variant 3-52814021-C-T is Benign according to our data. Variant chr3-52814021-C-T is described in ClinVar as Benign. ClinVar VariationId is 776472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00593 (8669/1461500) while in subpopulation SAS AF = 0.0177 (1526/86202). AF 95% confidence interval is 0.017. There are 59 homozygotes in GnomAdExome4. There are 4599 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITIH4	NM_002218.5	MANE Select	c.2677G>A	p.Gly893Ser	missense	Exon 23 of 24	NP_002209.2
	ITIH4	NM_001166449.2		c.2587G>A	p.Gly863Ser	missense	Exon 21 of 22	NP_001159921.1	Q14624-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITIH4	ENST00000266041.9	TSL:1 MANE Select	c.2677G>A	p.Gly893Ser	missense	Exon 23 of 24	ENSP00000266041.4	Q14624-1
ITIH4	ENST00000485816.5	TSL:1	c.2692G>A	p.Gly898Ser	missense	Exon 23 of 24	ENSP00000417824.1	B7ZKJ8
ITIH4	ENST00000441637.2	TSL:1	c.2041G>A	p.Gly681Ser	missense	Exon 17 of 18	ENSP00000395634.2	H7C0L5

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

599

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00553

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00522

AC:

1306

AN:

250400

AF XY:

0.00601

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00214

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00241

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00593

AC:

8669

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00633

AC XY:

4599

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33476

American (AMR)

AF:

0.00215

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0177

AC:

1526

AN:

86202

European-Finnish (FIN)

AF:

0.00227

AC:

121

AN:

53292

Middle Eastern (MID)

AF:

0.00490

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00585

AC:

6501

AN:

1111900

Other (OTH)

AF:

0.00545

AC:

329

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

460

920

1381

1841

2301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

252

504

756

1008

1260

<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:

0.00392

AC:

597

AN:

152302

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

302

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41570

American (AMR)

AF:

0.00373

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0153

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00551

AC:

375

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00436

Hom.:

Bravo

AF:

0.00313

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00577

AC:

700

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.00453

EpiControl

AF:

0.00587

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.36

(source)

DANN

Benign

0.43

DEOGEN2

Benign

0.035

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.7

PhyloP100

-0.24

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

REVEL

Benign

0.022

Sift

Benign

1.0

Sift4G

Benign

0.80

Polyphen

0.0

Vest4

0.057

MVP

0.32

MPC

0.27

ClinPred

0.00027

GERP RS

-0.98

Varity_R

0.031

gMVP

0.16

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over