rs9814951

Variant names:

• chr3-48573492-T-C
• rs9814951
• NM_000094.4:c.6618+21A>G

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.6618+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0502 in 1,613,920 control chromosomes in the GnomAD database, including 2,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (441 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2020 hom.)
• Consequence: COL7A1 NM_000094.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0650
• Publications: 15 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=-0.85).
• BP6: Variant 3-48573492-T-C is Benign according to our data. Variant chr3-48573492-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.6618+21A>G		intron_variant	Intron 83 of 118	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.6618+21A>G		intron_variant	Intron 83 of 118		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.6618+21A>G		intron_variant	Intron 82 of 117	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.2535+21A>G		intron_variant	Intron 48 of 82	5

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10251 AN: 152064 Hom.: 434 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0497

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0679

GnomAD2 exomes AF: 0.0584 AC: 14664 AN: 251300 AF XY: 0.0560

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0801

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0477

Gnomad NFE exome AF: 0.0447

Gnomad OTH exome AF: 0.0528

GnomAD4 exome AF: 0.0484 AC: 70803 AN: 1461738 Hom.: 2020 Cov.: 37 AF XY: 0.0484 AC XY: 35192 AN XY: 727154

African (AFR) AF: 0.115 AC: 3841 AN: 33478

American (AMR) AF: 0.0409 AC: 1830 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 2002 AN: 26134

East Asian (EAS) AF: 0.119 AC: 4718 AN: 39700

South Asian (SAS) AF: 0.0458 AC: 3950 AN: 86256

European-Finnish (FIN) AF: 0.0496 AC: 2648 AN: 53344

Middle Eastern (MID) AF: 0.0466 AC: 269 AN: 5768

European-Non Finnish (NFE) AF: 0.0431 AC: 47885 AN: 1111944

Other (OTH) AF: 0.0606 AC: 3660 AN: 60390

GnomAD4 genome AF: 0.0676 AC: 10289 AN: 152182 Hom.: 441 Cov.: 32 AF XY: 0.0668 AC XY: 4970 AN XY: 74408

African (AFR) AF: 0.109 AC: 4518 AN: 41504

American (AMR) AF: 0.0425 AC: 650 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 287 AN: 3470

East Asian (EAS) AF: 0.144 AC: 745 AN: 5180

South Asian (SAS) AF: 0.0489 AC: 236 AN: 4830

European-Finnish (FIN) AF: 0.0505 AC: 536 AN: 10614

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0456 AC: 3100 AN: 67974

Other (OTH) AF: 0.0738 AC: 156 AN: 2114

Alfa AF: 0.0519 Hom.: 498

Bravo AF: 0.0686

Asia WGS AF: 0.145 AC: 506 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.79
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs9814951; hg19: chr3-48610925; COSMIC: COSV60393018; COSMIC: COSV60393018;