10-104032161-C-A

Position:

• chr10-104032161-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000494.4(COL17A1):​c.*74G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,196,264 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (13 hom.)
• Consequence: COL17A1 NM_000494.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00800

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 (BayesDel_noAF=-0.59).
• BP6: Variant 10-104032161-C-A is Benign according to our data. Variant chr10-104032161-C-A is described in ClinVar as [Benign]. Clinvar id is 298677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00869 (1324/152310) while in subpopulation AFR AF= 0.0305 (1269/41566). AF 95% confidence interval is 0.0291. There are 23 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL17A1	NM_000494.4	c.*74G>T		3_prime_UTR_variant	56/56	ENST00000648076.2	NP_000485.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL17A1	ENST00000648076.2	c.*74G>T		3_prime_UTR_variant	56/56		NM_000494.4	ENSP00000497653	A2
COL17A1	ENST00000369733.8	c.*74G>T		3_prime_UTR_variant	51/51	5		ENSP00000358748	P4
COL17A1	ENST00000433822.1	c.*31+43G>T		intron_variant		5		ENSP00000388832
COL17A1	ENST00000647647.1	c.*638G>T		3_prime_UTR_variant, NMD_transcript_variant	5/5			ENSP00000497865

Frequencies

GnomAD3 genomes AF: 0.00871 AC: 1325 AN: 152192 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00101 AC: 1055 AN: 1043954 Hom.: 13 Cov.: 14 AF XY: 0.000871 AC XY: 468 AN XY: 537256

Gnomad4 AFR exome AF: 0.0317

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000519

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000151

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00869 AC: 1324 AN: 152310 Hom.: 23 Cov.: 32 AF XY: 0.00883 AC XY: 658 AN XY: 74486

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00656 Hom.: 1

Bravo AF: 0.00979

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.7
DANN	Benign	0.84

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: rs12253626; hg19: chr10-105791919;