NM_000213.5:c.5336T>C

Variant names:

• chr17-75757422-T-C
• rs871443
• NM_000213.5:c.5336T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.78
• Publications: 51 publications found

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]

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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health, Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000213.5. 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
	ITGB4	NM_000213.5	MANE Select	c.5336T>C	p.Leu1779Pro	missense	Exon 40 of 40	NP_000204.3
	ITGB4	NM_001005619.2		c.5285T>C	p.Leu1762Pro	missense	Exon 40 of 40	NP_001005619.1
	ITGB4	NM_001005731.3		c.5126T>C	p.Leu1709Pro	missense	Exon 39 of 39	NP_001005731.1	P16144-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB4	ENST00000200181.8	TSL:1 MANE Select	c.5336T>C	p.Leu1779Pro	missense	Exon 40 of 40	ENSP00000200181.3	P16144-1
	ITGB4	ENST00000449880.7	TSL:1	c.5285T>C	p.Leu1762Pro	missense	Exon 40 of 40	ENSP00000400217.2	P16144-3
	ITGB4	ENST00000450894.7	TSL:1	c.5126T>C	p.Leu1709Pro	missense	Exon 39 of 39	ENSP00000405536.3	P16144-2

Frequencies

GnomAD3 genomes AF: 0.627 AC: 95341 AN: 151966 Hom.: 33915 Cov.: 33

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

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.: 81 AF XY: 0.759 AC XY: 551853 AN XY: 726714

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

GnomAD4 genome AF: 0.627 AC: 95372 AN: 152084 Hom.: 33925 Cov.: 33 AF XY: 0.635 AC XY: 47219 AN XY: 74334

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Junctional epidermolysis bullosa with pyloric atresia (3)
-	-	3	not provided (3)
-	-	1	Deficiency of galactokinase (1)
-	-	1	Epidermolysis bullosa simplex 1C, localized (1)
-	-	1	Junctional epidermolysis bullosa, non-Herlitz type (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.60
Sift	Benign	0.097	T
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.20
MPC		0.88
ClinPred		0.016	T
GERP RS		4.2
PromoterAI		-0.012	Neutral
Varity_R		0.66
gMVP		0.83
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs871443; hg19: chr17-73753503; COSMIC: COSV52321862; COSMIC: COSV52321862;