rs7327728

Positions:

• chr13-110203747-A-T

Variant summary

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

The ENST00000375820.10(COL4A1):​c.958-140T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 854,052 control chromosomes in the GnomAD database, including 3,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2415 hom., cov: 34)
  • Exomes 𝑓: 0.026 (1212 hom.)
• Consequence: COL4A1 ENST00000375820.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.391

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-110203747-A-T is Benign according to our data. Variant chr13-110203747-A-T is described in ClinVar as [Benign]. Clinvar id is 1295700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.958-140T>A		intron_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.958-140T>A		intron_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.958-140T>A		intron_variant		1	NM_001845.6	ENSP00000364979	P1
COL4A1	ENST00000543140.6	c.958-140T>A		intron_variant		1		ENSP00000443348
COL4A1	ENST00000647797.1	c.837-140T>A		intron_variant				ENSP00000497756
COL4A1	ENST00000649738.1	n.1088-140T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16394 AN: 152138 Hom.: 2394 Cov.: 34

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0856

GnomAD4 exome AF: 0.0255 AC: 17899 AN: 701794 Hom.: 1212 AF XY: 0.0234 AC XY: 8637 AN XY: 369478

Gnomad4 AFR exome AF: 0.335

Gnomad4 AMR exome AF: 0.0326

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.0479

Gnomad4 SAS exome AF: 0.00843

Gnomad4 FIN exome AF: 0.00252

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.108 AC: 16461 AN: 152258 Hom.: 2415 Cov.: 34 AF XY: 0.103 AC XY: 7651 AN XY: 74452

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.0500

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.0636

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0922

Alfa AF: 0.0686 Hom.: 178

Bravo AF: 0.122

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.51

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: rs7327728; hg19: chr13-110856094;