ENST00000200181:c.-125G>C

Variant names:

• chr17-75721498-G-C
• rs552008042
• NM_000213.5:c.-125G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000200181.8(ITGB4):​c.-125G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 121,510 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITGB4 ENST00000200181.8 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.833
• Publications: 0 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]

ITGB4 Gene-Disease associations (from GenCC):

• epidermolysis bullosa simplex

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• junctional epidermolysis bullosa with pyloric atresia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Genomics England PanelApp
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• aplasia cutis congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• epidermolysis bullosa simplex 5C, with pyloric atresia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• localized junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• epidermolysis bullosa simplex 1C, localized

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-75721498-G-C is Benign according to our data. Variant chr17-75721498-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 325118.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00593 (721/121510) while in subpopulation NFE AF = 0.00779 (471/60472). AF 95% confidence interval is 0.00721. There are 6 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000200181.8. 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.-125G>C		5_prime_UTR	Exon 1 of 40	NP_000204.3
	ITGB4	NM_001005619.2		c.-125G>C		5_prime_UTR	Exon 1 of 40	NP_001005619.1
	ITGB4	NM_001005731.3		c.-125G>C		5_prime_UTR	Exon 1 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.-125G>C		5_prime_UTR	Exon 1 of 40	ENSP00000200181.3	P16144-1
	ITGB4	ENST00000449880.7	TSL:1	c.-125G>C		5_prime_UTR	Exon 1 of 40	ENSP00000400217.2	P16144-3
	ITGB4	ENST00000450894.7	TSL:1	c.-125G>C		5_prime_UTR	Exon 1 of 39	ENSP00000405536.3	P16144-2

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 722 AN: 121478 Hom.: 6 Cov.: 29

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00491

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.000557

Gnomad SAS AF: 0.00242

Gnomad FIN AF: 0.00247

Gnomad MID AF: 0.0352

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.0107

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 28

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 32

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00593 AC: 721 AN: 121510 Hom.: 6 Cov.: 29 AF XY: 0.00534 AC XY: 306 AN XY: 57282

African (AFR) AF: 0.00284 AC: 91 AN: 32054

American (AMR) AF: 0.00647 AC: 68 AN: 10502

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 37 AN: 3196

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3574

South Asian (SAS) AF: 0.00242 AC: 8 AN: 3312

European-Finnish (FIN) AF: 0.00247 AC: 14 AN: 5664

Middle Eastern (MID) AF: 0.0345 AC: 8 AN: 232

European-Non Finnish (NFE) AF: 0.00779 AC: 471 AN: 60472

Other (OTH) AF: 0.0107 AC: 18 AN: 1690

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00483

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Junctional epidermolysis bullosa with pyloric atresia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.6
DANN	Benign	0.78
PhyloP100		-0.83
PromoterAI		-0.094	Neutral
Mutation Taster		=294/6	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs552008042; hg19: chr17-73717578;