NM_000213.5:c.2986C>T

Variant names:

• chr17-75743736-C-T
• rs772142634
• NM_000213.5:c.2986C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000213.5(ITGB4):​c.2986C>T​(p.Gln996*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITGB4 NM_000213.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.29
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-75743736-C-T is Pathogenic according to our data. Variant chr17-75743736-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2986C>T	p.Gln996*	stop_gained	Exon 26 of 40	NP_000204.3
	ITGB4	NM_001005619.2		c.2986C>T	p.Gln996*	stop_gained	Exon 26 of 40	NP_001005619.1
	ITGB4	NM_001005731.3		c.2986C>T	p.Gln996*	stop_gained	Exon 26 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.2986C>T	p.Gln996*	stop_gained	Exon 26 of 40	ENSP00000200181.3	P16144-1
	ITGB4	ENST00000449880.7	TSL:1	c.2986C>T	p.Gln996*	stop_gained	Exon 26 of 40	ENSP00000400217.2	P16144-3
	ITGB4	ENST00000450894.7	TSL:1	c.2986C>T	p.Gln996*	stop_gained	Exon 26 of 39	ENSP00000405536.3	P16144-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250244 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461290 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Junctional epidermolysis bullosa with pyloric atresia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.3
Vest4		0.88
GERP RS		3.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs772142634; hg19: chr17-73739817;