NM_001845.6:c.780+7G>A

Variant names:

• chr13-110207396-C-T
• rs598893
• NM_001845.6:c.780+7G>A

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.780+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,607,206 control chromosomes in the GnomAD database, including 325,232 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 0.58 (26153 hom., cov: 32)
  • Exomes 𝑓: 0.64 (299079 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.000007063
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -3.17
• Publications: 19 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=-0.91).
• BP6: Variant 13-110207396-C-T is Benign according to our data. Variant chr13-110207396-C-T is described in ClinVar as Benign. ClinVar VariationId is 258262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 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.780+7G>A		splice_region intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.780+7G>A		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.780+7G>A		splice_region intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.780+7G>A		splice_region intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.780+7G>A		splice_region intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87531 AN: 151794 Hom.: 26156 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.620 AC: 155997 AN: 251422 AF XY: 0.632

Gnomad AFR exome AF: 0.414

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.757

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.638 AC: 928192 AN: 1455294 Hom.: 299079 Cov.: 33 AF XY: 0.641 AC XY: 464145 AN XY: 724398

African (AFR) AF: 0.402 AC: 13421 AN: 33362

American (AMR) AF: 0.498 AC: 22279 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 18367 AN: 26104

East Asian (EAS) AF: 0.772 AC: 30619 AN: 39676

South Asian (SAS) AF: 0.684 AC: 58886 AN: 86124

European-Finnish (FIN) AF: 0.607 AC: 32396 AN: 53410

Middle Eastern (MID) AF: 0.660 AC: 3796 AN: 5754

European-Non Finnish (NFE) AF: 0.642 AC: 709970 AN: 1106006

Other (OTH) AF: 0.639 AC: 38458 AN: 60154

GnomAD4 genome AF: 0.576 AC: 87543 AN: 151912 Hom.: 26153 Cov.: 32 AF XY: 0.578 AC XY: 42919 AN XY: 74238

African (AFR) AF: 0.422 AC: 17458 AN: 41394

American (AMR) AF: 0.544 AC: 8309 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.699 AC: 2427 AN: 3470

East Asian (EAS) AF: 0.758 AC: 3902 AN: 5146

South Asian (SAS) AF: 0.700 AC: 3372 AN: 4816

European-Finnish (FIN) AF: 0.610 AC: 6425 AN: 10528

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43360 AN: 67974

Other (OTH) AF: 0.619 AC: 1304 AN: 2108

Alfa AF: 0.626 Hom.: 44336

Bravo AF: 0.565

Asia WGS AF: 0.684 AC: 2380 AN: 3478

EpiCase AF: 0.656

EpiControl AF: 0.660

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)
-	-	3	not provided (3)
-	-	2	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.059
DANN	Benign	0.38
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
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: rs598893; hg19: chr13-110859743; COSMIC: COSV65426470;