17-75757422-T-C

Variant names:

Variant summary

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

The NM_000213.5(ITGB4):c.5336T>C(p.Leu1779Pro) variant causes a missense change. The variant allele was found at a frequency of 0.748 in 1,612,904 control chromosomes in the GnomAD database, including 462,348 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 33925 hom., cov: 33)

Exomes 𝑓: 0.76 ( 428423 hom. )

Consequence

ITGB4
NM_000213.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.78

Publications

51 publications found

Variant links:

Genes affected

ITGB4 (HGNC:6158): (integrin subunit beta 4) Integrins are heterodimers comprised of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ITGB4 links:

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

GALK1 Gene-Disease associations (from GenCC):

galactokinase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

GALK1 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=2.72673E-6).

BP6

Variant 17-75757422-T-C is Benign according to our data. Variant chr17-75757422-T-C is described in ClinVar as Benign. ClinVar VariationId is 255543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB4	NM_000213.5 link	c.5336T>C	p.Leu1779Pro	missense_variant	Exon 40 of 40	ENST00000200181.8	NP_000204.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB4	ENST00000200181.8 link	c.5336T>C	p.Leu1779Pro	missense_variant	Exon 40 of 40	1	NM_000213.5	ENSP00000200181.3

Frequencies

GnomAD3 genomes

AF:

0.627

AC:

95341

AN:

151966

Hom.:

33915

Cov.:

show subpopulations

Gnomad AFR

AF:

0.265

Gnomad AMI

AF:

0.705

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.681

Gnomad EAS

AF:

0.634

Gnomad SAS

AF:

0.735

Gnomad FIN

AF:

0.804

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.778

Gnomad OTH

AF:

0.663

GnomAD2 exomes

AF:

0.725

AC:

181328

AN:

250144

AF XY:

0.730

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.793

Gnomad ASJ exome

AF:

0.669

Gnomad EAS exome

AF:

0.638

Gnomad FIN exome

AF:

0.809

Gnomad NFE exome

AF:

0.775

Gnomad OTH exome

AF:

0.741

GnomAD4 exome

AF:

0.760

AC:

1110544

AN:

1460820

Hom.:

428423

Cov.:

AF XY:

0.759

AC XY:

551853

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.238

AC:

7980

AN:

33480

American (AMR)

AF:

0.791

AC:

35364

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.674

AC:

17625

AN:

26134

East Asian (EAS)

AF:

0.643

AC:

25531

AN:

39700

South Asian (SAS)

AF:

0.722

AC:

62318

AN:

86256

European-Finnish (FIN)

AF:

0.811

AC:

42539

AN:

52426

Middle Eastern (MID)

AF:

0.611

AC:

3526

AN:

5768

European-Non Finnish (NFE)

AF:

0.784

AC:

871386

AN:

1111962

Other (OTH)

AF:

0.733

AC:

44275

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

17805

35610

53415

71220

89025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20458

40916

61374

81832

102290

<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:

0.627

AC:

95372

AN:

152084

Hom.:

33925

Cov.:

AF XY:

0.635

AC XY:

47219

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.265

AC:

10971

AN:

41456

American (AMR)

AF:

0.761

AC:

11637

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.681

AC:

2363

AN:

3470

East Asian (EAS)

AF:

0.634

AC:

3274

AN:

5164

South Asian (SAS)

AF:

0.735

AC:

3548

AN:

4828

European-Finnish (FIN)

AF:

0.804

AC:

8525

AN:

10600

Middle Eastern (MID)

AF:

0.582

AC:

171

AN:

294

European-Non Finnish (NFE)

AF:

0.778

AC:

52845

AN:

67954

Other (OTH)

AF:

0.661

AC:

1395

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1475

2950

4426

5901

7376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

754

1508

2262

3016

3770

<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:

0.730

Hom.:

160786

Bravo

AF:

0.607

TwinsUK

AF:

0.772

AC:

2864

ALSPAC

AF:

0.786

AC:

3030

ESP6500AA

AF:

0.280

AC:

1235

ESP6500EA

AF:

0.769

AC:

6615

ExAC

AF:

0.713

AC:

86491

Asia WGS

AF:

0.665

AC:

2310

AN:

3478

EpiCase

AF:

0.760

EpiControl

AF:

0.764

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa with pyloric atresia

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epidermolysis bullosa simplex 1C, localized

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of galactokinase

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.19

.;T;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.81

.;T;T;T

MetaRNN

Benign

0.0000027

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

.;L;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.3

.;N;.;N

REVEL

Uncertain

0.60

Sift

Benign

0.097

.;T;.;T

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.99, 1.0

.;D;.;D

Vest4

0.20

MPC

0.88

ClinPred

0.016

GERP RS

4.2

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.66

gMVP

0.83

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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