3-48564341-A-G

Position:

• chr3-48564341-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000094.4(COL7A1):​c.*65T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,574,560 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.016 (294 hom.)
• Consequence: COL7A1 NM_000094.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.278

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-48564341-A-G is Benign according to our data. Variant chr3-48564341-A-G is described in ClinVar as [Benign]. Clinvar id is 345788.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48564341-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2169/152308) while in subpopulation NFE AF= 0.014 (954/68016). AF 95% confidence interval is 0.0133. There are 43 homozygotes in gnomad4. There are 1253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.*65T>C		3_prime_UTR_variant	119/119	ENST00000681320.1
COL7A1	XM_017005688.2	c.*65T>C		3_prime_UTR_variant	118/118

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.*65T>C		3_prime_UTR_variant	119/119		NM_000094.4	P1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2169 AN: 152190 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0160 AC: 22801 AN: 1422252 Hom.: 294 Cov.: 26 AF XY: 0.0158 AC XY: 11182 AN XY: 709838

Gnomad4 AFR exome AF: 0.00251

Gnomad4 AMR exome AF: 0.00505

Gnomad4 ASJ exome AF: 0.00716

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00911

Gnomad4 FIN exome AF: 0.0749

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0142 AC: 2169 AN: 152308 Hom.: 43 Cov.: 32 AF XY: 0.0168 AC XY: 1253 AN XY: 74486

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0140

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0138 Hom.: 4

Bravo AF: 0.00822

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.75
CADD	Benign	4.6
DANN	Benign	0.82

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

Other links and lift over

dbSNP: rs74780677; hg19: chr3-48601774;