rs7327728

Variant names:

• chr13-110203747-A-T
• rs7327728
• NM_001845.6:c.958-140T>A

Your query was ambiguous. Multiple possible variants found:

• chr13-110203747-A-T
• chr13-110203747-A-C

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.958-140T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 854,052 control chromosomes in the GnomAD database, including 3,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (2415 hom., cov: 34)
  • Exomes 𝑓: 0.026 (1212 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.391
• 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: Ambry Genetics, Orphanet, G2P, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• 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=-0.83).
• BP6: Variant 13-110203747-A-T is Benign according to our data. Variant chr13-110203747-A-T is described in ClinVar as Benign. ClinVar VariationId is 1295700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 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.958-140T>A		intron	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.958-140T>A		intron	N/A	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.958-140T>A		intron	N/A	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.958-140T>A		intron	N/A	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.958-140T>A		intron	N/A	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16394 AN: 152138 Hom.: 2394 Cov.: 34

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0502

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0414

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0856

GnomAD4 exome AF: 0.0255 AC: 17899 AN: 701794 Hom.: 1212 AF XY: 0.0234 AC XY: 8637 AN XY: 369478

African (AFR) AF: 0.335 AC: 6011 AN: 17934

American (AMR) AF: 0.0326 AC: 1089 AN: 33410

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 221 AN: 19330

East Asian (EAS) AF: 0.0479 AC: 1629 AN: 33994

South Asian (SAS) AF: 0.00843 AC: 527 AN: 62500

European-Finnish (FIN) AF: 0.00252 AC: 104 AN: 41264

Middle Eastern (MID) AF: 0.0536 AC: 207 AN: 3860

European-Non Finnish (NFE) AF: 0.0144 AC: 6555 AN: 454502

Other (OTH) AF: 0.0445 AC: 1556 AN: 35000

GnomAD4 genome AF: 0.108 AC: 16461 AN: 152258 Hom.: 2415 Cov.: 34 AF XY: 0.103 AC XY: 7651 AN XY: 74452

African (AFR) AF: 0.338 AC: 14040 AN: 41510

American (AMR) AF: 0.0500 AC: 765 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.0636 AC: 330 AN: 5192

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4824

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10610

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1023 AN: 68032

Other (OTH) AF: 0.0922 AC: 195 AN: 2114

Alfa AF: 0.0686 Hom.: 178

Bravo AF: 0.122

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.51
PhyloP100		0.39
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: rs7327728; hg19: chr13-110856094; COSMIC: COSV107488254; COSMIC: COSV107488254;