13-110205548-A-G

Variant names:

• chr13-110205548-A-G
• rs677877
• NM_001845.6:c.859-10T>C

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.859-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,610,452 control chromosomes in the GnomAD database, including 326,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26221 hom., cov: 32)
  • Exomes 𝑓: 0.64 (300359 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Scores: Splicing: ADA: 0.0004416
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.07
• Publications: 18 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=-0.83).
• BP6: Variant 13-110205548-A-G is Benign according to our data. Variant chr13-110205548-A-G is described in ClinVar as Benign. ClinVar VariationId is 258265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.741 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.859-10T>C		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.859-10T>C		intron	N/A	NP_001290039.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.859-10T>C		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.859-10T>C		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.859-10T>C		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87566 AN: 151050 Hom.: 26225 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.622 AC: 156273 AN: 251358 AF XY: 0.633

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.639 AC: 931871 AN: 1459286 Hom.: 300359 Cov.: 41 AF XY: 0.641 AC XY: 465778 AN XY: 726112

African (AFR) AF: 0.407 AC: 13484 AN: 33148

American (AMR) AF: 0.500 AC: 22360 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 18414 AN: 26112

East Asian (EAS) AF: 0.774 AC: 30727 AN: 39694

South Asian (SAS) AF: 0.684 AC: 58999 AN: 86204

European-Finnish (FIN) AF: 0.607 AC: 32402 AN: 53412

Middle Eastern (MID) AF: 0.660 AC: 3803 AN: 5764

European-Non Finnish (NFE) AF: 0.642 AC: 713100 AN: 1109992

Other (OTH) AF: 0.640 AC: 38582 AN: 60266

GnomAD4 genome AF: 0.579 AC: 87578 AN: 151166 Hom.: 26221 Cov.: 32 AF XY: 0.582 AC XY: 42947 AN XY: 73840

African (AFR) AF: 0.429 AC: 17407 AN: 40622

American (AMR) AF: 0.545 AC: 8331 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2429 AN: 3468

East Asian (EAS) AF: 0.761 AC: 3936 AN: 5170

South Asian (SAS) AF: 0.701 AC: 3373 AN: 4810

European-Finnish (FIN) AF: 0.610 AC: 6438 AN: 10552

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.638 AC: 43378 AN: 67962

Other (OTH) AF: 0.619 AC: 1303 AN: 2106

Alfa AF: 0.599 Hom.: 12762

Bravo AF: 0.566

Asia WGS AF: 0.686 AC: 2386 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)
-	-	2	Brain small vessel disease 1 with or without ocular anomalies (2)
-	-	2	not provided (2)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.46
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.010
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: rs677877; hg19: chr13-110857895; COSMIC: COSV104687934;