chr3-48590581-G-A

Position:

chr3-48590581-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.10 ( 972 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14226 hom. )

Consequence

COL7A1
NM_000094.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.742

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]

COL7A1 links:

COL7A1 (HGNC:):

COL7A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.002085656).

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	Protein	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.1784C>T	p.Pro595Leu	missense_variant	15/119	ENST00000681320.1	NP_000085.1	Q02388-1Q59F16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.1784C>T	p.Pro595Leu	missense_variant	15/119		NM_000094.4	ENSP00000506558.1		Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.1784C>T	p.Pro595Leu	missense_variant	14/118	1		ENSP00000332371.8		Q02388-1

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15590

AN:

152040

Hom.:

971

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.136

AC XY:

99030

AN XY:

727208

show subpopulations

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.:

AF XY:

0.103

AC XY:

7664

AN XY:

74392

show subpopulations

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 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

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.9

DANN

Benign

0.47

DEOGEN2

Benign

0.18

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.49

REVEL

Benign

0.10

Sift

Benign

0.41

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.042

MPC

0.25

ClinPred

0.000025

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over