rs2305080

Variant names:

• chr13-110186356-T-C
• rs2305080
• NM_001845.6:c.1897+29A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.1897+29A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,611,298 control chromosomes in the GnomAD database, including 107,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9921 hom., cov: 33)
  • Exomes 𝑓: 0.36 (97759 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.712
• Publications: 10 publications found

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]

COL4A1 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-110186356-T-C is Benign according to our data. Variant chr13-110186356-T-C is described in ClinVar as Benign. ClinVar VariationId is 1261039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.1897+29A>G		intron	N/A	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.1897+29A>G		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.1897+29A>G		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.1705+29A>G		intron	N/A	ENSP00000478222.3

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54848 AN: 152012 Hom.: 9904 Cov.: 33

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.366 AC: 90701 AN: 247764 AF XY: 0.363

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.353

GnomAD4 exome AF: 0.364 AC: 531200 AN: 1459168 Hom.: 97759 Cov.: 37 AF XY: 0.363 AC XY: 263589 AN XY: 725918

African (AFR) AF: 0.338 AC: 11294 AN: 33442

American (AMR) AF: 0.397 AC: 17769 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 8032 AN: 26128

East Asian (EAS) AF: 0.468 AC: 18584 AN: 39696

South Asian (SAS) AF: 0.337 AC: 28953 AN: 85940

European-Finnish (FIN) AF: 0.345 AC: 18101 AN: 52402

Middle Eastern (MID) AF: 0.265 AC: 1301 AN: 4912

European-Non Finnish (NFE) AF: 0.365 AC: 405369 AN: 1111664

Other (OTH) AF: 0.362 AC: 21797 AN: 60270

GnomAD4 genome AF: 0.361 AC: 54908 AN: 152130 Hom.: 9921 Cov.: 33 AF XY: 0.360 AC XY: 26788 AN XY: 74346

African (AFR) AF: 0.343 AC: 14225 AN: 41520

American (AMR) AF: 0.369 AC: 5649 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 1143 AN: 3466

East Asian (EAS) AF: 0.468 AC: 2412 AN: 5152

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4822

European-Finnish (FIN) AF: 0.342 AC: 3619 AN: 10584

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24779 AN: 67968

Other (OTH) AF: 0.375 AC: 792 AN: 2110

Alfa AF: 0.352 Hom.: 2018

Bravo AF: 0.364

Asia WGS AF: 0.418 AC: 1451 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.048
DANN	Benign	0.29
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2305080; hg19: chr13-110838703; COSMIC: COSV65429663; COSMIC: COSV65429663;