Variant chr3-48572667-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_000094.4(COL7A1):c.6900+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COL7A1
NM_000094.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.9788

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.46

Variant links:

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]

COL7A1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-48572667-T-C is Pathogenic according to our data. Variant chr3-48572667-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374314.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48572667-T-C is described in Lovd as [Likely_pathogenic]. Variant chr3-48572667-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4 linkuse as main transcript	c.6900+4A>G		splice_donor_region_variant, intron_variant		ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1 linkuse as main transcript	c.6900+4A>G	splice_donor_region_variant, intron_variant		NM_000094.4	P1	Q02388-1
COL7A1	ENST00000328333.12 linkuse as main transcript	c.6900+4A>G	splice_donor_region_variant, intron_variant	1		P1	Q02388-1
COL7A1	ENST00000487017.5 linkuse as main transcript	n.2817+4A>G	splice_donor_region_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1452080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 09, 2020

Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 16965329). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 10504458, 16965329, 17425959). ClinVar contains an entry for this variant (Variation ID: 374314). This sequence change falls in intron 87 of the COL7A1 gene. It does not directly change the encoded amino acid sequence of the COL7A1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). -

Generalized dominant dystrophic epidermolysis bullosa

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Baylor Genetics

May 01, 2016

Our laboratory has reported dual molecular diagnoses in COL7A1 (NM_000094.3:c.6900+4A>G) and DDX3X (NM_001356.3:c.1052G>A) in an individual with microcephaly, delayed motor milestones, delayed speech, hypotonia, hyperreflexia, repetitive behaviors, dysmorphic features, mild conductive hearing loss, mild epidermolysis bullosa (EB) and a history of prematurity and genital anomalies. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.58

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.58

Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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