NM_001845.6:c.1257T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001845.6(COL4A1):c.1257T>C(p.Pro419Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,652 control chromosomes in the GnomAD database, including 59,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P419P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.26 ( 5286 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54094 hom. )

Consequence

COL4A1
NM_001845.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.90

Publications

14 publications found

Variant links:

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

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 13-110198495-A-G is Benign according to our data. Variant chr13-110198495-A-G is described in ClinVar as Benign. ClinVar VariationId is 258246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.311 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.1257T>C	p.Pro419Pro	synonymous	Exon 21 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.1257T>C	p.Pro419Pro	synonymous	Exon 21 of 25	NP_001290039.1	P02462-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.1257T>C	p.Pro419Pro	synonymous	Exon 21 of 52	ENSP00000364979.4	P02462-1
COL4A1	ENST00000543140.6	TSL:1	c.1257T>C	p.Pro419Pro	synonymous	Exon 21 of 25	ENSP00000443348.1	P02462-2
COL4A1	ENST00000650424.2		c.1257T>C	p.Pro419Pro	synonymous	Exon 21 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38945

AN:

151882

Hom.:

5276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.0483

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.231

GnomAD2 exomes

AF:

0.260

AC:

65165

AN:

250958

AF XY:

0.256

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.0449

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.267

AC:

389888

AN:

1461652

Hom.:

54094

Cov.:

AF XY:

0.266

AC XY:

193177

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.222

AC:

7417

AN:

33478

American (AMR)

AF:

0.336

AC:

15002

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

6308

AN:

26134

East Asian (EAS)

AF:

0.0367

AC:

1456

AN:

39700

South Asian (SAS)

AF:

0.230

AC:

19878

AN:

86250

European-Finnish (FIN)

AF:

0.327

AC:

17426

AN:

53298

Middle Eastern (MID)

AF:

0.251

AC:

1439

AN:

5742

European-Non Finnish (NFE)

AF:

0.275

AC:

305860

AN:

1111946

Other (OTH)

AF:

0.250

AC:

15102

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

16845

33690

50536

67381

84226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10124

20248

30372

40496

50620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.257

AC:

38989

AN:

152000

Hom.:

5286

Cov.:

AF XY:

0.258

AC XY:

19204

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.218

AC:

9027

AN:

41462

American (AMR)

AF:

0.319

AC:

4866

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

854

AN:

3470

East Asian (EAS)

AF:

0.0481

AC:

248

AN:

5160

South Asian (SAS)

AF:

0.210

AC:

1010

AN:

4804

European-Finnish (FIN)

AF:

0.331

AC:

3495

AN:

10562

Middle Eastern (MID)

AF:

0.245

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.278

AC:

18868

AN:

67948

Other (OTH)

AF:

0.228

AC:

482

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1458

2916

4375

5833

7291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.251

Hom.:

2360

Bravo

AF:

0.251

Asia WGS

AF:

0.131

AC:

458

AN:

3478

EpiCase

AF:

0.263

EpiControl

AF:

0.259

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Brain small vessel disease 1 with or without ocular anomalies (3)

not provided (2)

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.015

(source)

DANN

Benign

0.44

PhyloP100

-2.9

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over