rs9588116

Variant names:

• chr13-110206722-G-C
• rs9588116
• NM_001845.6:c.808-7C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110206722-G-C
• chr13-110206722-G-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.808-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,612,834 control chromosomes in the GnomAD database, including 107,411 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 0.39 (11794 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95617 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001471
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.775
• Publications: 15 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=-0.86).
• BP6: Variant 13-110206722-G-C is Benign according to our data. Variant chr13-110206722-G-C is described in ClinVar as Benign. ClinVar VariationId is 258263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 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.808-7C>G		splice_region intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.808-7C>G		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.808-7C>G		splice_region intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.808-7C>G		splice_region intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.808-7C>G		splice_region intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58711 AN: 151782 Hom.: 11765 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.355

GnomAD2 exomes AF: 0.370 AC: 92962 AN: 251358 AF XY: 0.361

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.358 AC: 523198 AN: 1460936 Hom.: 95617 Cov.: 37 AF XY: 0.356 AC XY: 258613 AN XY: 726868

African (AFR) AF: 0.462 AC: 15451 AN: 33446

American (AMR) AF: 0.495 AC: 22142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7747 AN: 26134

East Asian (EAS) AF: 0.226 AC: 8979 AN: 39698

South Asian (SAS) AF: 0.316 AC: 27229 AN: 86218

European-Finnish (FIN) AF: 0.392 AC: 20958 AN: 53410

Middle Eastern (MID) AF: 0.335 AC: 1934 AN: 5766

European-Non Finnish (NFE) AF: 0.358 AC: 397508 AN: 1111180

Other (OTH) AF: 0.352 AC: 21250 AN: 60362

GnomAD4 genome AF: 0.387 AC: 58799 AN: 151898 Hom.: 11794 Cov.: 32 AF XY: 0.387 AC XY: 28728 AN XY: 74244

African (AFR) AF: 0.448 AC: 18559 AN: 41404

American (AMR) AF: 0.448 AC: 6828 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 1044 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1240 AN: 5164

South Asian (SAS) AF: 0.299 AC: 1440 AN: 4812

European-Finnish (FIN) AF: 0.389 AC: 4102 AN: 10536

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24609 AN: 67944

Other (OTH) AF: 0.359 AC: 757 AN: 2108

Alfa AF: 0.280 Hom.: 1040

Bravo AF: 0.404

EpiCase AF: 0.343

EpiControl AF: 0.340

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.37
DANN	Benign	0.30
PhyloP100		0.78
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0080
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: rs9588116; hg19: chr13-110859069; COSMIC: COSV65429672;