rs121912845
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP2PP3PP5_Very_Strong
The NM_000094.4(COL7A1):c.5096C>T(p.Pro1699Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,610,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
COL7A1
NM_000094.4 missense
NM_000094.4 missense
Scores
4
10
5
Splicing: ADA: 0.9904
2
Clinical Significance
Conservation
PhyloP100: 1.58
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PP2
Missense variant in the COL7A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 223 curated pathogenic missense variants (we use a threshold of 10). The gene has 262 curated benign missense variants. Gene score misZ: 1.5899 (below the threshold of 3.09). Trascript score misZ: 4.0428 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.818
PP5
Variant 3-48580301-G-A is Pathogenic according to our data. Variant chr3-48580301-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48580301-G-A is described in Lovd as [Pathogenic]. Variant chr3-48580301-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.5096C>T | p.Pro1699Leu | missense_variant | Exon 56 of 119 | NM_000094.4 | ENSP00000506558.1 | |||
COL7A1 | ENST00000328333.12 | c.5096C>T | p.Pro1699Leu | missense_variant | Exon 55 of 118 | 1 | ENSP00000332371.8 | |||
COL7A1 | ENST00000487017.5 | n.1013C>T | splice_region_variant, non_coding_transcript_exon_variant | Exon 21 of 83 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152086Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
2
AN:
152086
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000206 AC: 5AN: 242372Hom.: 0 AF XY: 0.0000228 AC XY: 3AN XY: 131478
GnomAD3 exomes
AF:
AC:
5
AN:
242372
Hom.:
AF XY:
AC XY:
3
AN XY:
131478
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000158 AC: 23AN: 1457856Hom.: 0 Cov.: 33 AF XY: 0.0000207 AC XY: 15AN XY: 724860
GnomAD4 exome
AF:
AC:
23
AN:
1457856
Hom.:
Cov.:
33
AF XY:
AC XY:
15
AN XY:
724860
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74394
GnomAD4 genome
AF:
AC:
2
AN:
152204
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
74394
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
4
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The COL7A1 p.P1699L variant was identified in the literature in a compound heterozygous individual with Dystrophic Epidermolysis Bullosa and a compound heterozygous individual with Aplasia Cutis Congenita in Bullous Dermolysis Gardella_2002_PMID:12485454; Diociaiuti_2016_PMID:26864810). The variant was identified in dbSNP (ID: rs121912845) and ClinVar (classified as pathogenic by OMIM). The variant was identified in control databases in 6 of 273692 chromosomes at a frequency of 0.00002192 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.P1699 residue is conserved in mammals and computational analyses (MUT Assesor, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) 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 (Splice AI exome) 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 29, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1699 of the COL7A1 protein (p.Pro1699Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive COL7A1-related conditions (PMID: 12485454, 26864810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17451). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL7A1 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 03, 2024 | - - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Mar 26, 2018 | - - |
Epidermolysis bullosa, pretibial, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2002 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at