rs142566193

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

Scores

3
12
4

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:2

Conservation

PhyloP100: 5.24
Variant links:
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 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
COL7A1NM_000094.4 linkuse as main transcriptc.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
COL7A1ENST00000681320.1 linkuse as main transcriptc.8371C>T p.Arg2791Trp missense_variant 114/119 NM_000094.4 ENSP00000506558 P1Q02388-1
COL7A1ENST00000328333.12 linkuse as main transcriptc.8371C>T p.Arg2791Trp missense_variant 113/1181 ENSP00000332371 P1Q02388-1
COL7A1ENST00000487017.5 linkuse as main transcriptn.5010C>T non_coding_transcript_exon_variant 78/835

Frequencies

GnomAD3 genomes
AF:
0.00106
AC:
161
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.000848
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00188
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00110
AC:
254
AN:
231330
Hom.:
2
AF XY:
0.00109
AC XY:
136
AN XY:
124510
show subpopulations
Gnomad AFR exome
AF:
0.000551
Gnomad AMR exome
AF:
0.000501
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000388
Gnomad FIN exome
AF:
0.000920
Gnomad NFE exome
AF:
0.00186
Gnomad OTH exome
AF:
0.00106
GnomAD4 exome
AF:
0.00162
AC:
2350
AN:
1452166
Hom.:
3
Cov.:
33
AF XY:
0.00155
AC XY:
1119
AN XY:
721322
show subpopulations
Gnomad4 AFR exome
AF:
0.000240
Gnomad4 AMR exome
AF:
0.000398
Gnomad4 ASJ exome
AF:
0.0000778
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000450
Gnomad4 FIN exome
AF:
0.000778
Gnomad4 NFE exome
AF:
0.00191
Gnomad4 OTH exome
AF:
0.00208
GnomAD4 genome
AF:
0.00106
AC:
161
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.000806
AC XY:
60
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.000848
Gnomad4 NFE
AF:
0.00188
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.00134
Hom.:
2
Bravo
AF:
0.00122
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00198
AC:
17
ExAC
AF:
0.00126
AC:
153

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 providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityOct 13, 2014- -
Pathogenic, criteria provided, single submitterclinical testingHUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP)-- -
not provided Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Uncertain significance, no assertion criteria providedclinical testingDepartment 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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 submitterclinical testingAmbry GeneticsSep 01, 2015- -
Epidermolysis bullosa dystrophica inversa, autosomal recessive Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
COL7A1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 08, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.081
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
28
DANN
Benign
0.97
DEOGEN2
Uncertain
0.70
D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.26
T
MetaSVM
Uncertain
0.36
D
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.73
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.89
MVP
0.95
MPC
0.92
ClinPred
0.063
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.21
gMVP
0.71

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs142566193; hg19: chr3-48603736; API