rs1778817

Variant names:

• chr13-110167113-G-A
• rs1778817
• NM_001845.6:c.3949+45C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110167113-G-A
• chr13-110167113-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.3949+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,531,910 control chromosomes in the GnomAD database, including 326,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29517 hom., cov: 31)
  • Exomes 𝑓: 0.66 (297455 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32
• Publications: 12 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=-0.92).
• BP6: Variant 13-110167113-G-A is Benign according to our data. Variant chr13-110167113-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.661 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.3949+45C>T		intron	N/A	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.3949+45C>T		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.3949+45C>T		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.3757+45C>T		intron	N/A	ENSP00000478222.3

Frequencies

GnomAD3 genomes AF: 0.620 AC: 93859 AN: 151390 Hom.: 29512 Cov.: 31

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.606

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.610

GnomAD2 exomes AF: 0.659 AC: 165593 AN: 251232 AF XY: 0.659

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.651

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.637

GnomAD4 exome AF: 0.655 AC: 904396 AN: 1380400 Hom.: 297455 Cov.: 22 AF XY: 0.655 AC XY: 453039 AN XY: 691556

African (AFR) AF: 0.499 AC: 15886 AN: 31846

American (AMR) AF: 0.715 AC: 31883 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 15422 AN: 25638

East Asian (EAS) AF: 0.649 AC: 25474 AN: 39276

South Asian (SAS) AF: 0.661 AC: 55876 AN: 84582

European-Finnish (FIN) AF: 0.729 AC: 38888 AN: 53314

Middle Eastern (MID) AF: 0.582 AC: 3169 AN: 5442

European-Non Finnish (NFE) AF: 0.655 AC: 680250 AN: 1038038

Other (OTH) AF: 0.651 AC: 37548 AN: 57652

GnomAD4 genome AF: 0.620 AC: 93905 AN: 151510 Hom.: 29517 Cov.: 31 AF XY: 0.625 AC XY: 46292 AN XY: 74052

African (AFR) AF: 0.512 AC: 21158 AN: 41288

American (AMR) AF: 0.670 AC: 10219 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2065 AN: 3468

East Asian (EAS) AF: 0.653 AC: 3338 AN: 5110

South Asian (SAS) AF: 0.680 AC: 3264 AN: 4800

European-Finnish (FIN) AF: 0.723 AC: 7582 AN: 10486

Middle Eastern (MID) AF: 0.603 AC: 175 AN: 290

European-Non Finnish (NFE) AF: 0.655 AC: 44397 AN: 67810

Other (OTH) AF: 0.614 AC: 1297 AN: 2112

Alfa AF: 0.631 Hom.: 6562

Bravo AF: 0.613

Asia WGS AF: 0.690 AC: 2401 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.44
DANN	Benign	0.52
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1778817; hg19: chr13-110819460;