rs142566193
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2
The NM_000094.4(COL7A1):c.8371C>T(p.Arg2791Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00157 in 1,604,438 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 3 hom. )
Consequence
COL7A1
NM_000094.4 missense
NM_000094.4 missense
Scores
3
12
4
Clinical Significance
Conservation
PhyloP100: 5.24
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
In a region_of_interest Nonhelical region (NC2) (size 159) in uniprot entity CO7A1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000094.4
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.
BP4
Computational evidence support a benign effect (MetaRNN=0.26036757).
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.8371C>T | p.Arg2791Trp | missense_variant | 114/119 | ENST00000681320.1 | NP_000085.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.8371C>T | p.Arg2791Trp | missense_variant | 114/119 | NM_000094.4 | ENSP00000506558 | P1 | ||
COL7A1 | ENST00000328333.12 | c.8371C>T | p.Arg2791Trp | missense_variant | 113/118 | 1 | ENSP00000332371 | P1 | ||
COL7A1 | ENST00000487017.5 | n.5010C>T | non_coding_transcript_exon_variant | 78/83 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00106 AC: 161AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00110 AC: 254AN: 231330Hom.: 2 AF XY: 0.00109 AC XY: 136AN XY: 124510
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GnomAD4 exome AF: 0.00162 AC: 2350AN: 1452166Hom.: 3 Cov.: 33 AF XY: 0.00155 AC XY: 1119AN XY: 721322
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GnomAD4 genome AF: 0.00106 AC: 161AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000806 AC XY: 60AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Recessive dystrophic epidermolysis bullosa Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Oct 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | HUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP) | - | - - |
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The COL7A1 p.Arg2791Trp variant was identified in the literature as a compound heterozygous variant in 1 of 14 patients with dystrophic epidermolysis bullosa (Dang_2007_PMID:17425959). The variant was also identified as a compound heterozygous variant in a 62 year old man with dystrophic epidermolysis bullosa who also carried a p.Gly1281Valfs*44 variant (Mahto_2013_PMID:23786535). The variant was identified in dbSNP (ID: rs142566193), ClinVar (classified as likely pathogenic by Knight Diagnostic Laboratories,Oregon Health and Sciences University, and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as pathogenic, likely pathogenic and VUS). The variant was identified in control databases in 284 of 262690 chromosomes (2 homozygous) at a frequency of 0.001081 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 213 of 120204 chromosomes (freq: 0.001772), Other in 8 of 6758 chromosomes (freq: 0.001184), European (Finnish) in 22 of 23032 chromosomes (freq: 0.000955), African in 14 of 23204 chromosomes (freq: 0.000603), Latino in 16 of 32778 chromosomes (freq: 0.000488) and South Asian in 11 of 28376 chromosomes (freq: 0.000388), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg2791 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Epidermolysis bullosa dystrophica Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2015 | - - |
Epidermolysis bullosa dystrophica inversa, autosomal recessive Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
COL7A1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 08, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at