13-110206969-GAAA-GA

Variant names:

• chr13-110206969-GAA-G
• rs60585275
• NM_001845.6:c.781-80_781-79delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001845.6(COL4A1):​c.781-80_781-79delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,159,466 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 18)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.323
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.781-80_781-79delTT		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.781-80_781-79delTT		intron	N/A	NP_001290039.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.781-80_781-79delTT		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.781-80_781-79delTT		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.781-80_781-79delTT		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.000328 AC: 46 AN: 140218 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.000896

Gnomad AMI AF: 0.00118

Gnomad AMR AF: 0.000354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000783

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000496 AC: 506 AN: 1019186 Hom.: 0 AF XY: 0.000508 AC XY: 263 AN XY: 517596

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00165 AC: 37 AN: 22412

American (AMR) AF: 0.000911 AC: 26 AN: 28526

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 6 AN: 19986

East Asian (EAS) AF: 0.0000634 AC: 2 AN: 31542

South Asian (SAS) AF: 0.000198 AC: 13 AN: 65782

European-Finnish (FIN) AF: 0.000440 AC: 20 AN: 45486

Middle Eastern (MID) AF: 0.000230 AC: 1 AN: 4348

European-Non Finnish (NFE) AF: 0.000506 AC: 383 AN: 757434

Other (OTH) AF: 0.000412 AC: 18 AN: 43670

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000328 AC: 46 AN: 140280 Hom.: 0 Cov.: 18 AF XY: 0.000323 AC XY: 22 AN XY: 68032

African (AFR) AF: 0.000894 AC: 34 AN: 38020

American (AMR) AF: 0.000354 AC: 5 AN: 14142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4626

South Asian (SAS) AF: 0.000228 AC: 1 AN: 4392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000783 AC: 5 AN: 63874

Other (OTH) AF: 0.00 AC: 0 AN: 1918

Alfa AF: 0.00 Hom.: 313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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: rs60585275; hg19: chr13-110859316;