rs9881877

Variant names:

• chr3-48575963-G-A
• rs9881877
• NM_000094.4:c.5821-61C>T

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.5821-61C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,612,342 control chromosomes in the GnomAD database, including 7,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3493 hom., cov: 33)
  • Exomes 𝑓: 0.048 (4422 hom.)
• Consequence: COL7A1 NM_000094.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0410
• Publications: 4 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=-0.9).
• BP6: Variant 3-48575963-G-A is Benign according to our data. Variant chr3-48575963-G-A is described in ClinVar as Benign. ClinVar VariationId is 1229441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.5821-61C>T		intron_variant	Intron 71 of 118	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.5821-61C>T		intron_variant	Intron 71 of 118		NM_000094.4	ENSP00000506558.1
COL7A1	ENST00000328333.12	c.5821-61C>T		intron_variant	Intron 70 of 117	1		ENSP00000332371.8
COL7A1	ENST00000487017.5	n.1738-61C>T		intron_variant	Intron 36 of 82	5

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21853 AN: 152034 Hom.: 3473 Cov.: 33

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.0837

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0491

Gnomad FIN AF: 0.0408

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.138

GnomAD4 exome AF: 0.0476 AC: 69575 AN: 1460190 Hom.: 4422 AF XY: 0.0467 AC XY: 33932 AN XY: 726462

African (AFR) AF: 0.415 AC: 13876 AN: 33452

American (AMR) AF: 0.0558 AC: 2494 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2986 AN: 26128

East Asian (EAS) AF: 0.0911 AC: 3615 AN: 39690

South Asian (SAS) AF: 0.0465 AC: 4011 AN: 86222

European-Finnish (FIN) AF: 0.0413 AC: 2197 AN: 53234

Middle Eastern (MID) AF: 0.137 AC: 790 AN: 5766

European-Non Finnish (NFE) AF: 0.0314 AC: 34878 AN: 1110678

Other (OTH) AF: 0.0784 AC: 4728 AN: 60334

GnomAD4 genome AF: 0.144 AC: 21921 AN: 152152 Hom.: 3493 Cov.: 33 AF XY: 0.142 AC XY: 10569 AN XY: 74394

African (AFR) AF: 0.394 AC: 16321 AN: 41452

American (AMR) AF: 0.0834 AC: 1275 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3470

East Asian (EAS) AF: 0.108 AC: 560 AN: 5172

South Asian (SAS) AF: 0.0489 AC: 236 AN: 4824

European-Finnish (FIN) AF: 0.0408 AC: 433 AN: 10618

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0343 AC: 2335 AN: 68004

Other (OTH) AF: 0.140 AC: 295 AN: 2112

Alfa AF: 0.102 Hom.: 351

Bravo AF: 0.159

Asia WGS AF: 0.148 AC: 515 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epidermolysis bullosa dystrophica Benign:1

Sep 14, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.33
PhyloP100		-0.041
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: rs9881877; hg19: chr3-48613396; COSMIC: COSV60393058; COSMIC: COSV60393058;