Genetic Variant NM_002217.4:c.943C>A (chr3-52799789-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002217.4(ITIH3):c.943C>A(p.Gln315Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,612,218 control chromosomes in the GnomAD database, including 179,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q315R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.53 ( 22824 hom., cov: 33)

Exomes 𝑓: 0.46 ( 156199 hom. )

Consequence

ITIH3
NM_002217.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.771

Publications

67 publications found

Variant links:

Genes affected

ITIH3 (HGNC:6168): (inter-alpha-trypsin inhibitor heavy chain 3) This gene encodes the heavy chain subunit of the pre-alpha-trypsin inhibitor complex. This complex may stabilize the extracellular matrix through its ability to bind hyaluronic acid. Polymorphisms of this gene may be associated with increased risk for schizophrenia and major depressive disorder. This gene is present in an inter-alpha-trypsin inhibitor family gene cluster on chromosome 3. [provided by RefSeq, Jul 2015]

ITIH3 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=1.9009592E-6).

BP6

Variant 3-52799789-C-A is Benign according to our data. Variant chr3-52799789-C-A is described in ClinVar as Benign. ClinVar VariationId is 1279402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH3	NM_002217.4 link	c.943C>A	p.Gln315Lys	missense_variant	Exon 9 of 22	ENST00000449956.3	NP_002208.3	Q06033-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH3	ENST00000449956.3 link	c.943C>A	p.Gln315Lys	missense_variant	Exon 9 of 22	1	NM_002217.4	ENSP00000415769.2		Q06033-1

Frequencies

GnomAD3 genomes

AF:

0.535

AC:

81217

AN:

151912

Hom.:

22790

Cov.:

show subpopulations

Gnomad AFR

AF:

0.712

Gnomad AMI

AF:

0.534

Gnomad AMR

AF:

0.580

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.420

Gnomad SAS

AF:

0.351

Gnomad FIN

AF:

0.424

Gnomad MID

AF:

0.472

Gnomad NFE

AF:

0.459

Gnomad OTH

AF:

0.511

GnomAD2 exomes

AF:

0.479

AC:

118451

AN:

247344

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.718

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.486

Gnomad EAS exome

AF:

0.408

Gnomad FIN exome

AF:

0.440

Gnomad NFE exome

AF:

0.462

Gnomad OTH exome

AF:

0.463

GnomAD4 exome

AF:

0.459

AC:

669504

AN:

1460190

Hom.:

156199

Cov.:

AF XY:

0.454

AC XY:

329916

AN XY:

726328

show subpopulations

African (AFR)

AF:

0.718

AC:

24016

AN:

33452

American (AMR)

AF:

0.602

AC:

26827

AN:

44576

Ashkenazi Jewish (ASJ)

AF:

0.495

AC:

12928

AN:

26118

East Asian (EAS)

AF:

0.458

AC:

18164

AN:

39684

South Asian (SAS)

AF:

0.344

AC:

29659

AN:

86154

European-Finnish (FIN)

AF:

0.437

AC:

23280

AN:

53218

Middle Eastern (MID)

AF:

0.456

AC:

2626

AN:

5762

European-Non Finnish (NFE)

AF:

0.454

AC:

504475

AN:

1110904

Other (OTH)

AF:

0.456

AC:

27529

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17350

34700

52050

69400

86750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15170

30340

45510

60680

75850

<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:

0.535

AC:

81309

AN:

152028

Hom.:

22824

Cov.:

AF XY:

0.531

AC XY:

39453

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.712

AC:

29507

AN:

41454

American (AMR)

AF:

0.580

AC:

8854

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1700

AN:

3470

East Asian (EAS)

AF:

0.420

AC:

2170

AN:

5166

South Asian (SAS)

AF:

0.351

AC:

1691

AN:

4820

European-Finnish (FIN)

AF:

0.424

AC:

4481

AN:

10564

Middle Eastern (MID)

AF:

0.473

AC:

139

AN:

294

European-Non Finnish (NFE)

AF:

0.459

AC:

31195

AN:

67964

Other (OTH)

AF:

0.513

AC:

1085

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1909

3818

5728

7637

9546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.484

Hom.:

90462

Bravo

AF:

0.557

TwinsUK

AF:

0.451

AC:

1671

ALSPAC

AF:

0.450

AC:

1733

ESP6500AA

AF:

0.710

AC:

2690

ESP6500EA

AF:

0.466

AC:

3852

ExAC

AF:

0.479

AC:

57829

Asia WGS

AF:

0.448

AC:

1555

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32712163) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.7

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.0035

T;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.018

T;T;T

MetaRNN

Benign

0.0000019

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.8

.;.;N

PhyloP100

0.77

PrimateAI

Benign

0.32

PROVEAN

Benign

1.5

.;N;N

REVEL

Benign

0.18

Sift

Benign

0.43

.;T;T

Sift4G

Benign

0.97

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.043

MPC

0.13

ClinPred

0.0051

GERP RS

4.2

Varity_R

0.11

gMVP

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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