chr13-110164824-G-C

Variant names:

• chr13-110164824-G-C
• rs1816884
• NM_001845.6:c.4150+38C>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.4150+38C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 1,607,758 control chromosomes in the GnomAD database, including 116,423 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9840 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106583 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33
• Publications: 8 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: Genomics England PanelApp, Orphanet, G2P, Ambry Genetics
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp
• 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=-0.91).
• BP6: Variant 13-110164824-G-C is Benign according to our data. Variant chr13-110164824-G-C is described in ClinVar as Benign. ClinVar VariationId is 1217362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.4150+38C>G		intron	N/A	NP_001836.3	P02462-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4150+38C>G		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.4150+38C>G		intron	N/A	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.4051+38C>G		intron	N/A	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52300 AN: 151974 Hom.: 9845 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.373

GnomAD2 exomes AF: 0.399 AC: 95724 AN: 240100 AF XY: 0.397

Gnomad AFR exome AF: 0.210

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.727

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.377 AC: 548568 AN: 1455668 Hom.: 106583 Cov.: 35 AF XY: 0.377 AC XY: 272532 AN XY: 723496

African (AFR) AF: 0.210 AC: 6978 AN: 33292

American (AMR) AF: 0.419 AC: 18460 AN: 44024

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10946 AN: 25942

East Asian (EAS) AF: 0.693 AC: 27386 AN: 39514

South Asian (SAS) AF: 0.380 AC: 32431 AN: 85274

European-Finnish (FIN) AF: 0.340 AC: 18006 AN: 53028

Middle Eastern (MID) AF: 0.442 AC: 2423 AN: 5480

European-Non Finnish (NFE) AF: 0.369 AC: 408861 AN: 1109022

Other (OTH) AF: 0.384 AC: 23077 AN: 60092

GnomAD4 genome AF: 0.344 AC: 52302 AN: 152090 Hom.: 9840 Cov.: 32 AF XY: 0.348 AC XY: 25891 AN XY: 74344

African (AFR) AF: 0.216 AC: 8967 AN: 41490

American (AMR) AF: 0.395 AC: 6041 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1439 AN: 3472

East Asian (EAS) AF: 0.728 AC: 3757 AN: 5158

South Asian (SAS) AF: 0.406 AC: 1956 AN: 4822

European-Finnish (FIN) AF: 0.338 AC: 3575 AN: 10576

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25223 AN: 67970

Other (OTH) AF: 0.370 AC: 781 AN: 2110

Alfa AF: 0.362 Hom.: 1861

Bravo AF: 0.346

Asia WGS AF: 0.512 AC: 1777 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	-	1	Brain small vessel disease 1 with or without ocular anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.47
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1816884;

hg19: chr13-110817171;

COSMIC: COSV65431654;

COSMIC: COSV65431654;