rs17256786

Variant names:

• chr3-48566583-C-G
• rs17256786
• NM_000094.4:c.8305-20G>C

Variant summary

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

The NM_000094.4(COL7A1):​c.8305-20G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0648 in 1,614,112 control chromosomes in the GnomAD database, including 3,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (268 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3429 hom.)
• Consequence: COL7A1 NM_000094.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.664
• Publications: 9 publications found

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

COL7A1 Gene-Disease associations (from GenCC):

• epidermolysis bullosa with congenital localized absence of skin and deformity of nails

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• dystrophic epidermolysis bullosa pruriginosa

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• recessive dystrophic epidermolysis bullosa

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, ClinGen
• generalized dominant dystrophic epidermolysis bullosa

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet
• pretibial dystrophic epidermolysis bullosa

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• transient bullous dermolysis of the newborn

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• acral dystrophic epidermolysis bullosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dystrophic epidermolysis bullosa, nails only

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• recessive dystrophic epidermolysis bullosa inversa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive dystrophic epidermolysis bullosa-generalized other

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-48566583-C-G is Benign according to our data. Variant chr3-48566583-C-G is described in ClinVar as Benign. ClinVar VariationId is 255114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000094.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	NM_000094.4	MANE Select	c.8305-20G>C		intron	N/A	NP_000085.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	ENST00000681320.1	MANE Select	c.8305-20G>C		intron	N/A	ENSP00000506558.1
	COL7A1	ENST00000328333.12	TSL:1	c.8305-20G>C		intron	N/A	ENSP00000332371.8
	COL7A1	ENST00000474432.1	TSL:3	n.705-20G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0509 AC: 7738 AN: 152150 Hom.: 268 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0877

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0459

GnomAD2 exomes AF: 0.0539 AC: 13542 AN: 251462 AF XY: 0.0540

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.0722

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.0763

Gnomad OTH exome AF: 0.0586

GnomAD4 exome AF: 0.0662 AC: 96820 AN: 1461844 Hom.: 3429 Cov.: 38 AF XY: 0.0650 AC XY: 47252 AN XY: 727230

African (AFR) AF: 0.0102 AC: 340 AN: 33480

American (AMR) AF: 0.0334 AC: 1493 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 1860 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0192 AC: 1659 AN: 86258

European-Finnish (FIN) AF: 0.0882 AC: 4712 AN: 53418

Middle Eastern (MID) AF: 0.0376 AC: 217 AN: 5766

European-Non Finnish (NFE) AF: 0.0747 AC: 83041 AN: 1111972

Other (OTH) AF: 0.0579 AC: 3494 AN: 60394

GnomAD4 genome AF: 0.0508 AC: 7734 AN: 152268 Hom.: 268 Cov.: 32 AF XY: 0.0508 AC XY: 3784 AN XY: 74446

African (AFR) AF: 0.0138 AC: 573 AN: 41558

American (AMR) AF: 0.0453 AC: 694 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 245 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4822

European-Finnish (FIN) AF: 0.0877 AC: 931 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0736 AC: 5005 AN: 67994

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0629 Hom.: 61

Bravo AF: 0.0469

Asia WGS AF: 0.00924 AC: 34 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17256786; hg19: chr3-48604016; COSMIC: COSV56476420; COSMIC: COSV56476420;