chr3-48564341-A-G

Variant names:

• chr3-48564341-A-G
• rs74780677
• NM_000094.4:c.*65T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000094.4(COL7A1):​c.*65T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,574,560 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.016 (294 hom.)
• Consequence: COL7A1 NM_000094.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.278
• Publications: 7 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: 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: Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, ClinGen
• generalized dominant dystrophic epidermolysis bullosa

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

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

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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=-0.75).
• BP6: Variant 3-48564341-A-G is Benign according to our data. Variant chr3-48564341-A-G is described in ClinVar as Benign. ClinVar VariationId is 345788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2169/152308) while in subpopulation NFE AF = 0.014 (954/68016). AF 95% confidence interval is 0.0133. There are 43 homozygotes in GnomAd4. There are 1253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	NM_000094.4	MANE Select	c.*65T>C		3_prime_UTR	Exon 119 of 119	NP_000085.1	Q02388-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL7A1	ENST00000681320.1	MANE Select	c.*65T>C		3_prime_UTR	Exon 119 of 119	ENSP00000506558.1	Q02388-1
	COL7A1	ENST00000328333.12	TSL:1	c.*65T>C		3_prime_UTR	Exon 118 of 118	ENSP00000332371.8	Q02388-1
	COL7A1	ENST00000465238.5	TSL:2	n.319T>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2169 AN: 152190 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0160 AC: 22801 AN: 1422252 Hom.: 294 Cov.: 26 AF XY: 0.0158 AC XY: 11182 AN XY: 709838

African (AFR) AF: 0.00251 AC: 82 AN: 32630

American (AMR) AF: 0.00505 AC: 225 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00716 AC: 185 AN: 25854

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39482

South Asian (SAS) AF: 0.00911 AC: 777 AN: 85294

European-Finnish (FIN) AF: 0.0749 AC: 3974 AN: 53078

Middle Eastern (MID) AF: 0.00596 AC: 34 AN: 5702

European-Non Finnish (NFE) AF: 0.0155 AC: 16698 AN: 1076630

Other (OTH) AF: 0.0140 AC: 824 AN: 58988

GnomAD4 genome AF: 0.0142 AC: 2169 AN: 152308 Hom.: 43 Cov.: 32 AF XY: 0.0168 AC XY: 1253 AN XY: 74486

African (AFR) AF: 0.00284 AC: 118 AN: 41568

American (AMR) AF: 0.00510 AC: 78 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4830

European-Finnish (FIN) AF: 0.0869 AC: 923 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 954 AN: 68016

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0138 Hom.: 4

Bravo AF: 0.00822

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epidermolysis bullosa dystrophica (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.6
DANN	Benign	0.82
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism

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: rs74780677; hg19: chr3-48601774;