10-104036641-G-C

Variant names:

• chr10-104036641-G-C
• rs2274098
• NM_000494.4:c.3278-9C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000494.4(COL17A1):​c.3278-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 1,612,920 control chromosomes in the GnomAD database, including 532,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (42098 hom., cov: 33)
  • Exomes 𝑓: 0.82 (490540 hom.)
• Consequence: COL17A1 NM_000494.4 intron
• Scores: Splicing: ADA: 0.003205
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.655
• Publications: 12 publications found

Genes affected

COL17A1 (HGNC:2194): (collagen type XVII alpha 1 chain) This gene encodes the alpha chain of type XVII collagen. Unlike most collagens, collagen XVII is a transmembrane protein. Collagen XVII is a structural component of hemidesmosomes, multiprotein complexes at the dermal-epidermal basement membrane zone that mediate adhesion of keratinocytes to the underlying membrane. Mutations in this gene are associated with both generalized atrophic benign and junctional epidermolysis bullosa. Two homotrimeric forms of type XVII collagen exist. The full length form is the transmembrane protein. A soluble form, referred to as either ectodomain or LAD-1, is generated by proteolytic processing of the full length form. [provided by RefSeq, Jul 2008]

COL17A1 Gene-Disease associations (from GenCC):

• epithelial recurrent erosion dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• epidermolysis bullosa, junctional 4, intermediate

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, G2P
• junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amelogenesis imperfecta

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• generalized junctional epidermolysis bullosa non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• late-onset junctional epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• localized junctional epidermolysis bullosa, non-Herlitz type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-104036641-G-C is Benign according to our data. Variant chr10-104036641-G-C is described in ClinVar as Benign. ClinVar VariationId is 256274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000494.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	NM_000494.4	MANE Select	c.3278-9C>G		intron	N/A	NP_000485.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL17A1	ENST00000648076.2	MANE Select	c.3278-9C>G		intron	N/A	ENSP00000497653.1	Q9UMD9-1
	COL17A1	ENST00000859462.1		c.3278-9C>G		intron	N/A	ENSP00000529521.1
	COL17A1	ENST00000859464.1		c.3275-9C>G		intron	N/A	ENSP00000529523.1

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110985 AN: 151982 Hom.: 42104 Cov.: 33

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.795

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.840

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.770

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.833

Gnomad OTH AF: 0.757

GnomAD2 exomes AF: 0.786 AC: 195786 AN: 249126 AF XY: 0.788

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.791

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.769

Gnomad NFE exome AF: 0.830

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.817 AC: 1193492 AN: 1460820 Hom.: 490540 Cov.: 61 AF XY: 0.815 AC XY: 592261 AN XY: 726700

African (AFR) AF: 0.484 AC: 16194 AN: 33466

American (AMR) AF: 0.791 AC: 35278 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 21428 AN: 26124

East Asian (EAS) AF: 0.839 AC: 33292 AN: 39690

South Asian (SAS) AF: 0.730 AC: 62879 AN: 86180

European-Finnish (FIN) AF: 0.772 AC: 41119 AN: 53232

Middle Eastern (MID) AF: 0.778 AC: 4297 AN: 5526

European-Non Finnish (NFE) AF: 0.837 AC: 930814 AN: 1111654

Other (OTH) AF: 0.799 AC: 48191 AN: 60332

GnomAD4 genome AF: 0.730 AC: 111006 AN: 152100 Hom.: 42098 Cov.: 33 AF XY: 0.729 AC XY: 54221 AN XY: 74346

African (AFR) AF: 0.501 AC: 20771 AN: 41456

American (AMR) AF: 0.795 AC: 12158 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2900 AN: 3472

East Asian (EAS) AF: 0.841 AC: 4349 AN: 5174

South Asian (SAS) AF: 0.710 AC: 3433 AN: 4832

European-Finnish (FIN) AF: 0.770 AC: 8171 AN: 10608

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.833 AC: 56603 AN: 67942

Other (OTH) AF: 0.751 AC: 1586 AN: 2112

Alfa AF: 0.803 Hom.: 15168

Bravo AF: 0.724

Asia WGS AF: 0.727 AC: 2525 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Junctional epidermolysis bullosa, non-Herlitz type (2)
-	-	1	Epithelial recurrent erosion dystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.5
DANN	Benign	0.64
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2274098; hg19: chr10-105796399;