rs74390291

chr3-48583059-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000094.4(COL7A1):c.4483-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,613,966 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (106 hom.)
• Consequence: COL7A1 NM_000094.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.5456
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.03

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 3-48583059-A-G is Benign according to our data. Variant chr3-48583059-A-G is described in ClinVar as [Benign]. Clinvar id is 255110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48583059-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00771 (1173/152138) while in subpopulation NFE AF= 0.0116 (791/67972). AF 95% confidence interval is 0.011. There are 9 homozygotes in gnomad4. There are 598 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.4483-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.4483-11T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_000094.4	P1
COL7A1	ENST00000328333.12	c.4483-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1		P1
COL7A1	ENST00000487017.5	n.400-11T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1173 AN: 152020 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00768 AC: 1930 AN: 251416 Hom.: 12 AF XY: 0.00770 AC XY: 1047 AN XY: 135900

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.0113 AC: 16503 AN: 1461828 Hom.: 106 Cov.: 34 AF XY: 0.0110 AC XY: 8001 AN XY: 727218

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00374

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00771 AC: 1173 AN: 152138 Hom.: 9 Cov.: 32 AF XY: 0.00804 AC XY: 598 AN XY: 74380

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00876 Hom.: 3

Bravo AF: 0.00666

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Epidermolysis bullosa dystrophica Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	16
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.55
dbscSNV1_RF	Benign	0.42
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

Other links and lift over

dbSNP: rs74390291; hg19: chr3-48620492;