3-52814021-C-T

Variant names:

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. 15/22 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

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 id 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 FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH4	NM_002218.5 link	c.2677G>A	p.Gly893Ser	missense_variant	Exon 23 of 24	ENST00000266041.9	NP_002209.2	Q14624-1B7ZKJ8B2RMS9
ITIH4	NM_001166449.2 link	c.2587G>A	p.Gly863Ser	missense_variant	Exon 21 of 22		NP_001159921.1	Q14624-3B7ZKJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ITIH4	ENST00000266041.9 link	c.2677G>A	p.Gly893Ser	missense_variant	Exon 23 of 24	1	NM_002218.5	ENSP00000266041.4	Q14624-1
ENSG00000243696	ENST00000468472.1 link	n.*4313G>A		non_coding_transcript_exon_variant	Exon 23 of 24	2		ENSP00000422253.1	D6R8Y8
ENSG00000243696	ENST00000468472.1 link	n.*4313G>A		3_prime_UTR_variant	Exon 23 of 24	2		ENSP00000422253.1	D6R8Y8

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

Gnomad4 AFR exome

AF:

0.000747

AC:

AN:

33476

Gnomad4 AMR exome

AF:

0.00215

AC:

AN:

44708

Gnomad4 ASJ exome

AF:

0.00161

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39694

Gnomad4 SAS exome

AF:

0.0177

AC:

1526

AN:

86202

Gnomad4 FIN exome

AF:

0.00227

AC:

121

AN:

53292

Gnomad4 NFE exome

AF:

0.00585

AC:

6501

AN:

1111900

Gnomad4 Remaining exome

AF:

0.00545

AC:

329

AN:

60372

Heterozygous variant carriers

460

920

1381

1841

2301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Gnomad4 AFR

AF:

0.00111

AC:

0.00110657

AN:

0.00110657

Gnomad4 AMR

AF:

0.00373

AC:

0.00372549

AN:

0.00372549

Gnomad4 ASJ

AF:

0.00202

AC:

0.00201613

AN:

0.00201613

Gnomad4 EAS

AF:

0.000193

AC:

0.000192901

AN:

0.000192901

Gnomad4 SAS

AF:

0.0153

AC:

0.0153463

AN:

0.0153463

Gnomad4 FIN

AF:

0.00264

AC:

0.00263952

AN:

0.00263952

Gnomad4 NFE

AF:

0.00551

AC:

0.00551244

AN:

0.00551244

Gnomad4 OTH

AF:

0.00331

AC:

0.00331439

AN:

0.00331439

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.36

DANN

Benign

0.43

DEOGEN2

Benign

0.035

T;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.57

T;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.7

N;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.022

Sift

Benign

1.0

T;T;T

Sift4G

Benign

0.80

T;T;T

Polyphen

0.0

B;B;.

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

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