rs2228561

chr3-48590581-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.1784C>T(p.Pro595Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,976 control chromosomes in the GnomAD database, including 15,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P595P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (972 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14226 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.742

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=0.002085656).
• BP6: Variant 3-48590581-G-A is Benign according to our data. Variant chr3-48590581-G-A is described in ClinVar as [Benign]. Clinvar id is 255103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48590581-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.1784C>T	p.Pro595Leu	missense_variant	15/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.1784C>T	p.Pro595Leu	missense_variant	15/119		NM_000094.4	P1
COL7A1	ENST00000328333.12	c.1784C>T	p.Pro595Leu	missense_variant	14/118	1		P1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15590 AN: 152040 Hom.: 971 Cov.: 32

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.0695

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.0892

GnomAD3 exomes AF: 0.117 AC: 29334 AN: 251310 Hom.: 2080 AF XY: 0.124 AC XY: 16875 AN XY: 135846

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.0714

Gnomad ASJ exome AF: 0.0971

Gnomad EAS exome AF: 0.0256

Gnomad SAS exome AF: 0.214

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.134 AC: 195720 AN: 1461818 Hom.: 14226 Cov.: 36 AF XY: 0.136 AC XY: 99030 AN XY: 727208

Gnomad4 AFR exome AF: 0.0459

Gnomad4 AMR exome AF: 0.0726

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.0199

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.102 AC: 15591 AN: 152158 Hom.: 972 Cov.: 32 AF XY: 0.103 AC XY: 7664 AN XY: 74392

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.0693

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.122 Hom.: 3046

Bravo AF: 0.0927

TwinsUK AF: 0.139 AC: 514

ALSPAC AF: 0.143 AC: 553

ESP6500AA AF: 0.0538 AC: 237

ESP6500EA AF: 0.127 AC: 1093

ExAC AF: 0.119 AC: 14462

Asia WGS AF: 0.117 AC: 409 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermolysis bullosa dystrophica Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -

not provided Benign:2

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

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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; rdeb, 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	0.074
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	3.9
Dann	Benign	0.47
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.10
Sift	Benign	0.41	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.25
ClinPred		0.000025	T
GERP RS		-3.0
Varity_R		0.020
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2228561; hg19: chr3-48628014; COSMIC: COSV60395678;