chr13-110209324-T-C

Variant names:

• chr13-110209324-T-C
• rs7333204
• NM_001845.6:c.651+68A>G

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.651+68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,379,242 control chromosomes in the GnomAD database, including 47,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5499 hom., cov: 32)
  • Exomes 𝑓: 0.25 (42066 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.422
• Publications: 4 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=-0.86).
• BP6: Variant 13-110209324-T-C is Benign according to our data. Variant chr13-110209324-T-C is described in ClinVar as Benign. ClinVar VariationId is 1293042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.651+68A>G		intron_variant	Intron 11 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.651+68A>G		intron_variant	Intron 11 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.651+68A>G		intron_variant	Intron 11 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40175 AN: 151768 Hom.: 5491 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0619

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.253 AC: 310833 AN: 1227356 Hom.: 42066 AF XY: 0.253 AC XY: 157043 AN XY: 621300

African (AFR) AF: 0.268 AC: 7376 AN: 27544

American (AMR) AF: 0.326 AC: 12377 AN: 38010

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 5608 AN: 23794

East Asian (EAS) AF: 0.0321 AC: 1241 AN: 38688

South Asian (SAS) AF: 0.227 AC: 17398 AN: 76680

European-Finnish (FIN) AF: 0.312 AC: 16543 AN: 52944

Middle Eastern (MID) AF: 0.257 AC: 1336 AN: 5200

European-Non Finnish (NFE) AF: 0.259 AC: 236177 AN: 912068

Other (OTH) AF: 0.244 AC: 12777 AN: 52428

GnomAD4 genome AF: 0.265 AC: 40219 AN: 151886 Hom.: 5499 Cov.: 32 AF XY: 0.266 AC XY: 19775 AN XY: 74240

African (AFR) AF: 0.269 AC: 11164 AN: 41426

American (AMR) AF: 0.320 AC: 4884 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 845 AN: 3470

East Asian (EAS) AF: 0.0455 AC: 235 AN: 5166

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4810

European-Finnish (FIN) AF: 0.321 AC: 3378 AN: 10524

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.266 AC: 18077 AN: 67906

Other (OTH) AF: 0.228 AC: 482 AN: 2116

Alfa AF: 0.259 Hom.: 7680

Bravo AF: 0.262

Asia WGS AF: 0.133 AC: 465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.43
PhyloP100		-0.42
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: rs7333204; hg19: chr13-110861671; COSMIC: COSV65423079;