rs41275104

Variant names:

• chr13-110242745-A-G
• rs41275104
• NM_001845.6:c.85-11T>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.85-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,186 control chromosomes in the GnomAD database, including 35,354 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4349 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31005 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Scores: Splicing: ADA: 0.00004950
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.830
• Publications: 7 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: Genomics England PanelApp, Orphanet, Ambry Genetics, G2P, PanelApp Australia
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, 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=-0.92).
• BP6: Variant 13-110242745-A-G is Benign according to our data. Variant chr13-110242745-A-G is described in ClinVar as Benign. ClinVar VariationId is 258264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 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.85-11T>C		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.85-11T>C		intron	N/A	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.85-11T>C		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.85-11T>C		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.85-11T>C		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33781 AN: 152096 Hom.: 4343 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.00864

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.215

GnomAD2 exomes AF: 0.178 AC: 44779 AN: 251298 AF XY: 0.183

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.0843

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.00762

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.177

GnomAD4 exome AF: 0.199 AC: 290851 AN: 1460972 Hom.: 31005 Cov.: 33 AF XY: 0.201 AC XY: 145729 AN XY: 726804

African (AFR) AF: 0.367 AC: 12264 AN: 33452

American (AMR) AF: 0.0917 AC: 4099 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4292 AN: 26134

East Asian (EAS) AF: 0.00554 AC: 220 AN: 39698

South Asian (SAS) AF: 0.235 AC: 20306 AN: 86246

European-Finnish (FIN) AF: 0.138 AC: 7359 AN: 53350

Middle Eastern (MID) AF: 0.236 AC: 1359 AN: 5768

European-Non Finnish (NFE) AF: 0.206 AC: 228811 AN: 1111238

Other (OTH) AF: 0.201 AC: 12141 AN: 60362

GnomAD4 genome AF: 0.222 AC: 33827 AN: 152214 Hom.: 4349 Cov.: 33 AF XY: 0.215 AC XY: 16016 AN XY: 74418

African (AFR) AF: 0.346 AC: 14377 AN: 41506

American (AMR) AF: 0.135 AC: 2058 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 550 AN: 3472

East Asian (EAS) AF: 0.00886 AC: 46 AN: 5194

South Asian (SAS) AF: 0.220 AC: 1063 AN: 4826

European-Finnish (FIN) AF: 0.124 AC: 1314 AN: 10602

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13687 AN: 68008

Other (OTH) AF: 0.214 AC: 452 AN: 2114

Alfa AF: 0.209 Hom.: 769

Bravo AF: 0.228

Asia WGS AF: 0.117 AC: 411 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	-	1	Brain small vessel disease 1 with or without ocular anomalies (1)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.3
DANN	Benign	0.47
PhyloP100		-0.83
PromoterAI		0.046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs41275104; hg19: chr13-110895092;