rs35761247

chr3-48585691-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000094.4(COL7A1):c.3830C>T(p.Pro1277Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0518 in 1,613,924 control chromosomes in the GnomAD database, including 2,524 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1277P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (157 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2367 hom.)
• Consequence: COL7A1 NM_000094.4 missense, splice_region
• Scores: Splicing: ADA: 0.07784
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.53

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL7A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.012060225).
• BP6: Variant 3-48585691-G-A is Benign according to our data. Variant chr3-48585691-G-A is described in ClinVar as [Benign]. Clinvar id is 255109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48585691-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	31/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	31/119		NM_000094.4	P1
COL7A1	ENST00000328333.12	c.3830C>T	p.Pro1277Leu	missense_variant, splice_region_variant	30/118	1		P1

Frequencies

GnomAD3 genomes AF: 0.0394 AC: 5999 AN: 152092 Hom.: 156 Cov.: 32

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0321

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.0868

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0431 AC: 10825 AN: 251336 Hom.: 318 AF XY: 0.0455 AC XY: 6178 AN XY: 135854

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.0269

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0546

Gnomad FIN exome AF: 0.0857

Gnomad NFE exome AF: 0.0493

Gnomad OTH exome AF: 0.0440

GnomAD4 exome AF: 0.0531 AC: 77627 AN: 1461714 Hom.: 2367 Cov.: 34 AF XY: 0.0531 AC XY: 38636 AN XY: 727156

Gnomad4 AFR exome AF: 0.00774

Gnomad4 AMR exome AF: 0.0261

Gnomad4 ASJ exome AF: 0.0335

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.0570

Gnomad4 FIN exome AF: 0.0825

Gnomad4 NFE exome AF: 0.0564

Gnomad4 OTH exome AF: 0.0513

GnomAD4 genome AF: 0.0394 AC: 5997 AN: 152210 Hom.: 157 Cov.: 32 AF XY: 0.0401 AC XY: 2985 AN XY: 74406

Gnomad4 AFR AF: 0.00963

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.0380

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.0483

Gnomad4 FIN AF: 0.0868

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0461 Hom.: 185

Bravo AF: 0.0319

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0418 AC: 5076

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0495

EpiControl AF: 0.0474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Epidermolysis bullosa dystrophica Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Recessive dystrophic epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Benign - Stand Alone, for Epidermolysis bullosa dystrophica, autosomal recessive, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Benign	0.97
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.014	D
Sift4G	Benign	0.067	T
Polyphen		1.0	D
Vest4		0.22
MPC		0.25
ClinPred		0.024	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.078
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs35761247; hg19: chr3-48623124;