rs148411473

Positions:

• chr3-48589399-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000094.4(COL7A1):​c.2242G>A​(p.Glu748Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,730 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (43 hom.)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.947

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL7A1. . Gene score misZ 1.5899 (greater than the threshold 3.09). Trascript score misZ 4.0428 (greater than threshold 3.09). GenCC has associacion of gene with recessive dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa pruriginosa, recessive dystrophic epidermolysis bullosa-generalized other, transient bullous dermolysis of the newborn, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, generalized dominant dystrophic epidermolysis bullosa, dystrophic epidermolysis bullosa, nails only, acral dystrophic epidermolysis bullosa, recessive dystrophic epidermolysis bullosa inversa, pretibial dystrophic epidermolysis bullosa.
• BP4: Computational evidence support a benign effect (MetaRNN=0.011641651).
• BP6: Variant 3-48589399-C-T is Benign according to our data. Variant chr3-48589399-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48589399-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00149 (227/152304) while in subpopulation SAS AF= 0.0151 (73/4828). AF 95% confidence interval is 0.0123. There are 1 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL7A1	NM_000094.4	c.2242G>A	p.Glu748Lys	missense_variant	18/119	ENST00000681320.1	NP_000085.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL7A1	ENST00000681320.1	c.2242G>A	p.Glu748Lys	missense_variant	18/119		NM_000094.4	ENSP00000506558	P1
COL7A1	ENST00000328333.12	c.2242G>A	p.Glu748Lys	missense_variant	17/118	1		ENSP00000332371	P1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00319 AC: 801 AN: 250884 Hom.: 10 AF XY: 0.00408 AC XY: 554 AN XY: 135748

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00183 AC: 2670 AN: 1461426 Hom.: 43 Cov.: 36 AF XY: 0.00241 AC XY: 1753 AN XY: 727046

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000683

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00176 AC XY: 131 AN XY: 74470

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00108

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Epidermolysis bullosa dystrophica 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.19
Sift	Benign	0.23	T
Sift4G	Benign	0.14	T
Polyphen		0.96	D
Vest4		0.49
MVP		0.82
MPC		0.28
ClinPred		0.016	T
GERP RS		5.3
Varity_R		0.098
gMVP		0.30

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: rs148411473; hg19: chr3-48626832;