chr10-104050613-T-G

Variant names:

• chr10-104050613-T-G
• rs138724889
• NM_000494.4:c.2128+8A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000494.4(COL17A1):​c.2128+8A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,612,974 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (14 hom.)
• Consequence: COL17A1 NM_000494.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003305
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.30

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 10-104050613-T-G is Benign according to our data. Variant chr10-104050613-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 298718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00198 (302/152194) while in subpopulation AMR AF = 0.00563 (86/15284). AF 95% confidence interval is 0.00467. There are 2 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.2128+8A>C		splice_region_variant, intron_variant	Intron 27 of 55	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.2128+8A>C		splice_region_variant, intron_variant	Intron 27 of 55		NM_000494.4	ENSP00000497653.1
COL17A1	ENST00000369733.8	c.2128+8A>C		splice_region_variant, intron_variant	Intron 26 of 50	5		ENSP00000358748.3

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152076 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00268 AC: 674 AN: 251486 AF XY: 0.00279

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00191 AC: 2796 AN: 1460780 Hom.: 14 Cov.: 31 AF XY: 0.00200 AC XY: 1453 AN XY: 726704

African (AFR) AF: 0.000478 AC: 16 AN: 33452

American (AMR) AF: 0.00463 AC: 207 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 327 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00319 AC: 275 AN: 86204

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53420

Middle Eastern (MID) AF: 0.0299 AC: 145 AN: 4848

European-Non Finnish (NFE) AF: 0.00139 AC: 1541 AN: 1112004

Other (OTH) AF: 0.00420 AC: 253 AN: 60292

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152194 Hom.: 2 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74412

African (AFR) AF: 0.000265 AC: 11 AN: 41536

American (AMR) AF: 0.00563 AC: 86 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4802

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 67996

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00283 Hom.: 2

Bravo AF: 0.00251

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL17A1: BP4, BS2 -

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.53
DANN	Benign	0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs138724889; hg19: chr10-105810371;