Genetic Variant NM_030569.7:c.1708A>C (chr10-7576723-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_030569.7(ITIH5):c.1708A>C(p.Thr570Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,736 control chromosomes in the GnomAD database, including 239,970 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.51 ( 20260 hom., cov: 32)

Exomes 𝑓: 0.55 ( 219710 hom. )

Consequence

ITIH5
NM_030569.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.115

Publications

33 publications found

Variant links:

Genes affected

ITIH5 (HGNC:21449): (inter-alpha-trypsin inhibitor heavy chain 5) This gene encodes a heavy chain component of one of the inter-alpha-trypsin inhibitor (ITI) family members. ITI proteins are involved in extracellular matrix stabilization and in the prevention of tumor metastasis. They are also structurally related plasma serine protease inhibitors and are composed of a light chain and varying numbers of heavy chains. This family member is thought to function as a tumor suppressor in breast and thyroid cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ITIH5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5562256E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITIH5	NM_030569.7 link	c.1708A>C	p.Thr570Pro	missense_variant	Exon 10 of 14	ENST00000397146.7	NP_085046.5	Q86UX2C9J2H1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITIH5	ENST00000397146.7 link	c.1708A>C	p.Thr570Pro	missense_variant	Exon 10 of 14	1	NM_030569.7	ENSP00000380333.3		C9J2H1

Frequencies

GnomAD3 genomes

AF:

0.510

AC:

77518

AN:

151892

Hom.:

20251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.408

Gnomad AMI

AF:

0.425

Gnomad AMR

AF:

0.525

Gnomad ASJ

AF:

0.497

Gnomad EAS

AF:

0.773

Gnomad SAS

AF:

0.545

Gnomad FIN

AF:

0.594

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.537

Gnomad OTH

AF:

0.493

GnomAD2 exomes

AF:

0.550

AC:

138172

AN:

251014

AF XY:

0.550

show subpopulations

Gnomad AFR exome

AF:

0.400

Gnomad AMR exome

AF:

0.547

Gnomad ASJ exome

AF:

0.503

Gnomad EAS exome

AF:

0.783

Gnomad FIN exome

AF:

0.591

Gnomad NFE exome

AF:

0.539

Gnomad OTH exome

AF:

0.525

GnomAD4 exome

AF:

0.546

AC:

797955

AN:

1461726

Hom.:

219710

Cov.:

AF XY:

0.545

AC XY:

396037

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.405

AC:

13562

AN:

33480

American (AMR)

AF:

0.544

AC:

24318

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.503

AC:

13142

AN:

26134

East Asian (EAS)

AF:

0.770

AC:

30555

AN:

39700

South Asian (SAS)

AF:

0.530

AC:

45674

AN:

86256

European-Finnish (FIN)

AF:

0.592

AC:

31574

AN:

53358

Middle Eastern (MID)

AF:

0.435

AC:

2509

AN:

5768

European-Non Finnish (NFE)

AF:

0.544

AC:

604344

AN:

1111946

Other (OTH)

AF:

0.534

AC:

32277

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

22808

45617

68425

91234

114042

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17222

34444

51666

68888

86110

<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:

0.510

AC:

77565

AN:

152010

Hom.:

20260

Cov.:

AF XY:

0.517

AC XY:

38387

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.408

AC:

16904

AN:

41458

American (AMR)

AF:

0.525

AC:

8019

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.497

AC:

1726

AN:

3472

East Asian (EAS)

AF:

0.773

AC:

3977

AN:

5144

South Asian (SAS)

AF:

0.546

AC:

2631

AN:

4818

European-Finnish (FIN)

AF:

0.594

AC:

6284

AN:

10586

Middle Eastern (MID)

AF:

0.397

AC:

116

AN:

292

European-Non Finnish (NFE)

AF:

0.537

AC:

36481

AN:

67930

Other (OTH)

AF:

0.492

AC:

1040

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1947

3893

5840

7786

9733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<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:

0.528

Hom.:

52371

Bravo

AF:

0.504

TwinsUK

AF:

0.557

AC:

2065

ALSPAC

AF:

0.549

AC:

2115

ESP6500AA

AF:

0.407

AC:

1795

ESP6500EA

AF:

0.538

AC:

4630

ExAC

AF:

0.546

AC:

66248

Asia WGS

AF:

0.605

AC:

2106

AN:

3478

EpiCase

AF:

0.525

EpiControl

AF:

0.524

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.1

(source)

DANN

Benign

0.087

DEOGEN2

Benign

0.0026

T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.015

T;T;T

MetaRNN

Benign

0.0000016

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.12

PrimateAI

Benign

0.26

PROVEAN

Benign

1.4

N;.;N

REVEL

Benign

0.029

Sift

Benign

1.0

T;.;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.019

ClinPred

0.0018

GERP RS

1.3

gMVP

0.58

Mutation Taster

=98/2

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

Computational scores

Splicing

Publications

Other links and lift over