NM_001845.6:c.234+8C>T

Variant names:

• chr13-110213918-G-A
• rs9521650
• NM_001845.6:c.234+8C>T

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.234+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,246 control chromosomes in the GnomAD database, including 18,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1564 hom., cov: 31)
  • Exomes 𝑓: 0.15 (17207 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002697
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.56
• Publications: 16 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: Ambry Genetics, Orphanet, G2P, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• 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 13-110213918-G-A is Benign according to our data. Variant chr13-110213918-G-A is described in ClinVar as Benign. ClinVar VariationId is 196328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 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.234+8C>T		splice_region intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.234+8C>T		splice_region 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.234+8C>T		splice_region intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.234+8C>T		splice_region intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.234+8C>T		splice_region intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20943 AN: 151752 Hom.: 1563 Cov.: 31

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.0898

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.159

GnomAD2 exomes AF: 0.141 AC: 35523 AN: 251490 AF XY: 0.142

Gnomad AFR exome AF: 0.0882

Gnomad AMR exome AF: 0.0969

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.151 AC: 220619 AN: 1461376 Hom.: 17207 Cov.: 33 AF XY: 0.149 AC XY: 108622 AN XY: 727030

African (AFR) AF: 0.0887 AC: 2969 AN: 33474

American (AMR) AF: 0.102 AC: 4564 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3788 AN: 26134

East Asian (EAS) AF: 0.220 AC: 8724 AN: 39696

South Asian (SAS) AF: 0.0879 AC: 7578 AN: 86250

European-Finnish (FIN) AF: 0.130 AC: 6946 AN: 53416

Middle Eastern (MID) AF: 0.143 AC: 827 AN: 5768

European-Non Finnish (NFE) AF: 0.158 AC: 176144 AN: 1111536

Other (OTH) AF: 0.150 AC: 9079 AN: 60378

GnomAD4 genome AF: 0.138 AC: 20952 AN: 151870 Hom.: 1564 Cov.: 31 AF XY: 0.138 AC XY: 10238 AN XY: 74244

African (AFR) AF: 0.0933 AC: 3863 AN: 41422

American (AMR) AF: 0.132 AC: 2007 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3468

East Asian (EAS) AF: 0.232 AC: 1194 AN: 5146

South Asian (SAS) AF: 0.0907 AC: 434 AN: 4786

European-Finnish (FIN) AF: 0.137 AC: 1442 AN: 10526

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10747 AN: 67958

Other (OTH) AF: 0.157 AC: 330 AN: 2104

Alfa AF: 0.151 Hom.: 3597

Bravo AF: 0.138

Asia WGS AF: 0.130 AC: 452 AN: 3478

EpiCase AF: 0.162

EpiControl AF: 0.167

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Brain small vessel disease 1 with or without ocular anomalies (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.49
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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: rs9521650; hg19: chr13-110866265; COSMIC: COSV65423024;