rs805708

chr10-104064575-G-A

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.629C>T(p.Thr210Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,612,832 control chromosomes in the GnomAD database, including 386,527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T210T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.60 (29359 hom., cov: 31)
  • Exomes 𝑓: 0.70 (357168 hom.)
• Consequence: COL17A1 NM_000494.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.27

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=5.8837804E-6).
• BP6: Variant 10-104064575-G-A is Benign according to our data. Variant chr10-104064575-G-A is described in ClinVar as [Benign]. Clinvar id is 256276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-104064575-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL17A1	NM_000494.4	c.629C>T	p.Thr210Met	missense_variant	10/56	ENST00000648076.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL17A1	ENST00000648076.2	c.629C>T	p.Thr210Met	missense_variant	10/56		NM_000494.4	A2

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91272 AN: 151980 Hom.: 29361 Cov.: 31

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.673

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.676 AC: 168590 AN: 249226 Hom.: 58370 AF XY: 0.677 AC XY: 91205 AN XY: 134696

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.770

Gnomad ASJ exome AF: 0.684

Gnomad EAS exome AF: 0.690

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.686

GnomAD4 exome AF: 0.696 AC: 1016503 AN: 1460736 Hom.: 357168 Cov.: 48 AF XY: 0.695 AC XY: 504716 AN XY: 726584

Gnomad4 AFR exome AF: 0.330

Gnomad4 AMR exome AF: 0.760

Gnomad4 ASJ exome AF: 0.688

Gnomad4 EAS exome AF: 0.708

Gnomad4 SAS exome AF: 0.637

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.712

Gnomad4 OTH exome AF: 0.673

GnomAD4 genome AF: 0.600 AC: 91284 AN: 152096 Hom.: 29359 Cov.: 31 AF XY: 0.602 AC XY: 44749 AN XY: 74366

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.696

Gnomad4 EAS AF: 0.689

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.673

Gnomad4 NFE AF: 0.707

Gnomad4 OTH AF: 0.615

Alfa AF: 0.687 Hom.: 89996

Bravo AF: 0.593

TwinsUK AF: 0.712 AC: 2640

ALSPAC AF: 0.714 AC: 2753

ESP6500AA AF: 0.355 AC: 1564

ESP6500EA AF: 0.703 AC: 6046

ExAC AF: 0.666 AC: 80816

Asia WGS AF: 0.569 AC: 1980 AN: 3478

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

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	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.74	T;.;T;T;T
MetaRNN	Benign	0.0000059	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L;L;L;.;.
MutationTaster	Benign	0.62	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D;D;.;.;D
REVEL	Benign	0.27
Sift	Benign	0.090	T;T;.;.;T
Sift4G	Pathogenic	0.0010	D;D;.;.;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.76
MPC		0.068
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.20

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: rs805708; hg19: chr10-105824333;