NM_000094.4:c.2005C>G

Variant names:

• chr3-48590258-G-C
• rs780261665
• NM_000094.4:c.2005C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000094.4(COL7A1):​c.2005C>G​(p.Arg669Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R669Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.888
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2005C>G	p.Arg669Gly	missense	Exon 16 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.2005C>G	p.Arg669Gly	missense	Exon 16 of 119	ENSP00000506558.1	Q02388-1
	COL7A1	ENST00000328333.12	TSL:1	c.2005C>G	p.Arg669Gly	missense	Exon 15 of 118	ENSP00000332371.8	Q02388-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461624 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727118

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 AN: 44704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.58
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.89
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.24
Sift	Benign	0.15	T
Sift4G	Uncertain	0.023	D
Polyphen		0.80	P
Vest4		0.64
MutPred		0.54		Loss of methylation at R669 (P = 0.0491)
MVP		0.70
MPC		0.32
ClinPred		0.38	T
GERP RS		2.7
Varity_R		0.16
gMVP		0.36
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs780261665; hg19: chr3-48627691;