rs17116350

Positions:

• chr10-104033992-T-C
• chr10-104033992-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000494.4(COL17A1):​c.4109A>G​(p.Asp1370Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,936 control chromosomes in the GnomAD database, including 50,100 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 (★★). Synonymous variant affecting the same amino acid position (i.e. D1370D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.28 (6098 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44002 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.157

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024353564).
• BP6: Variant 10-104033992-T-C is Benign according to our data. Variant chr10-104033992-T-C is described in ClinVar as [Benign]. Clinvar id is 256275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL17A1	NM_000494.4	c.4109A>G	p.Asp1370Gly	missense_variant	52/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.4109A>G	p.Asp1370Gly	missense_variant	52/56		NM_000494.4	A2
COL17A1	ENST00000369733.8	c.3863A>G	p.Asp1288Gly	missense_variant	47/51	5		P4
COL17A1	ENST00000647647.1	c.140A>G	p.Asp47Gly	missense_variant, NMD_transcript_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42141 AN: 151950 Hom.: 6090 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.258

GnomAD3 exomes AF: 0.244 AC: 61207 AN: 251344 Hom.: 7803 AF XY: 0.243 AC XY: 33002 AN XY: 135870

Gnomad AFR exome AF: 0.375

Gnomad AMR exome AF: 0.228

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.248

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.244 AC: 356318 AN: 1461866 Hom.: 44002 Cov.: 39 AF XY: 0.243 AC XY: 176755 AN XY: 727238

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.249

Gnomad4 NFE exome AF: 0.244

Gnomad4 OTH exome AF: 0.245

GnomAD4 genome AF: 0.277 AC: 42171 AN: 152070 Hom.: 6098 Cov.: 32 AF XY: 0.275 AC XY: 20441 AN XY: 74330

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.250

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.241

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.258

Alfa AF: 0.250 Hom.: 8860

Bravo AF: 0.281

TwinsUK AF: 0.249 AC: 925

ALSPAC AF: 0.261 AC: 1005

ESP6500AA AF: 0.374 AC: 1649

ESP6500EA AF: 0.247 AC: 2126

ExAC AF: 0.248 AC: 30111

Asia WGS AF: 0.193 AC: 671 AN: 3478

EpiCase AF: 0.255

EpiControl AF: 0.253

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Epithelial recurrent erosion dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.67
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.32	T;.;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.44	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.54	T;T;.
Sift4G	Benign	0.67	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.020
MPC		0.085
ClinPred		0.00040	T
GERP RS		-0.37
Varity_R		0.046
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs17116350; hg19: chr10-105793750; COSMIC: COSV59823759; COSMIC: COSV59823759;