rs503053

Variant names:

• chr13-110179104-T-C
• rs503053
• NM_001845.6:c.2345-68A>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110179104-T-C
• chr13-110179104-T-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.2345-68A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,535,320 control chromosomes in the GnomAD database, including 108,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12972 hom., cov: 32)
  • Exomes 𝑓: 0.37 (95567 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.520
• Publications: 6 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=-0.89).
• BP6: Variant 13-110179104-T-C is Benign according to our data. Variant chr13-110179104-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2345-68A>G		intron_variant	Intron 30 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2345-68A>G		intron_variant	Intron 30 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.408 AC: 61911 AN: 151872 Hom.: 12943 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.405

GnomAD4 exome AF: 0.369 AC: 510955 AN: 1383328 Hom.: 95567 Cov.: 22 AF XY: 0.369 AC XY: 254926 AN XY: 691386

African (AFR) AF: 0.520 AC: 16606 AN: 31932

American (AMR) AF: 0.404 AC: 17195 AN: 42542

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8192 AN: 25482

East Asian (EAS) AF: 0.265 AC: 10317 AN: 38982

South Asian (SAS) AF: 0.375 AC: 31374 AN: 83738

European-Finnish (FIN) AF: 0.356 AC: 18635 AN: 52340

Middle Eastern (MID) AF: 0.283 AC: 1360 AN: 4810

European-Non Finnish (NFE) AF: 0.369 AC: 385800 AN: 1045828

Other (OTH) AF: 0.372 AC: 21476 AN: 57674

GnomAD4 genome AF: 0.408 AC: 62001 AN: 151992 Hom.: 12972 Cov.: 32 AF XY: 0.406 AC XY: 30142 AN XY: 74316

African (AFR) AF: 0.514 AC: 21267 AN: 41410

American (AMR) AF: 0.386 AC: 5911 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3466

East Asian (EAS) AF: 0.300 AC: 1543 AN: 5144

South Asian (SAS) AF: 0.373 AC: 1797 AN: 4818

European-Finnish (FIN) AF: 0.351 AC: 3713 AN: 10578

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25122 AN: 67964

Other (OTH) AF: 0.410 AC: 865 AN: 2112

Alfa AF: 0.318 Hom.: 1255

Bravo AF: 0.415

Asia WGS AF: 0.381 AC: 1323 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.23
PhyloP100		-0.52
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: rs503053; hg19: chr13-110831451;