13-110206969-GAAA-GAA

Variant names:

• chr13-110206969-GA-G
• rs60585275
• NM_001845.6:c.781-79delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.781-79delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,144,856 control chromosomes in the GnomAD database, including 14,618 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (5032 hom., cov: 18)
  • Exomes 𝑓: 0.25 (9586 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.896
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 13-110206969-GA-G is Benign according to our data. Variant chr13-110206969-GA-G is described in ClinVar as Benign. ClinVar VariationId is 1250990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.328 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.781-79delT		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.781-79delT		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.781-79delT		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.781-79delT		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.781-79delT		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.272 AC: 38126 AN: 140118 Hom.: 5022 Cov.: 18

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.0696

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.237

GnomAD4 exome AF: 0.254 AC: 254724 AN: 1004676 Hom.: 9586 AF XY: 0.253 AC XY: 129133 AN XY: 510168

African (AFR) AF: 0.233 AC: 5148 AN: 22114

American (AMR) AF: 0.322 AC: 9072 AN: 28148

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 4715 AN: 19690

East Asian (EAS) AF: 0.0480 AC: 1471 AN: 30626

South Asian (SAS) AF: 0.228 AC: 14793 AN: 65016

European-Finnish (FIN) AF: 0.309 AC: 13864 AN: 44844

Middle Eastern (MID) AF: 0.269 AC: 1153 AN: 4286

European-Non Finnish (NFE) AF: 0.260 AC: 193947 AN: 746942

Other (OTH) AF: 0.246 AC: 10561 AN: 43010

GnomAD4 genome AF: 0.272 AC: 38172 AN: 140180 Hom.: 5032 Cov.: 18 AF XY: 0.276 AC XY: 18785 AN XY: 67978

African (AFR) AF: 0.252 AC: 9560 AN: 37984

American (AMR) AF: 0.336 AC: 4744 AN: 14126

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 850 AN: 3308

East Asian (EAS) AF: 0.0517 AC: 239 AN: 4626

South Asian (SAS) AF: 0.226 AC: 992 AN: 4388

European-Finnish (FIN) AF: 0.362 AC: 3209 AN: 8872

Middle Eastern (MID) AF: 0.279 AC: 77 AN: 276

European-Non Finnish (NFE) AF: 0.282 AC: 17991 AN: 63834

Other (OTH) AF: 0.235 AC: 451 AN: 1918

Alfa AF: 0.153 Hom.: 313

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.90
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: rs60585275; hg19: chr13-110859316; COSMIC: COSV65423633;