rs375318302

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1BP4

The NM_001845.6(COL4A1):c.2093A>G(p.Lys698Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,611,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense, splice_region

Scores

Splicing: ADA: 0.04646

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 7.29

Publications

1 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: Genomics England PanelApp, Orphanet, Ambry Genetics, G2P, PanelApp Australia
autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, 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

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_001845.6

BP4

Computational evidence support a benign effect (MetaRNN=0.39705947).

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.2093A>G	p.Lys698Arg	missense splice_region	Exon 28 of 52	NP_001836.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.2093A>G	p.Lys698Arg	missense splice_region	Exon 28 of 52	ENSP00000364979.4
COL4A1	ENST00000650424.2		c.2093A>G	p.Lys698Arg	missense splice_region	Exon 28 of 52	ENSP00000497477.2
COL4A1	ENST00000933608.1		c.2093A>G	p.Lys698Arg	missense splice_region	Exon 28 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000493

AC:

AN:

243308

AF XY:

0.0000226

show subpopulations

Gnomad AFR exome

AF:

0.000473

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000910

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1459798

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726050

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33454

American (AMR)

AF:

0.0000898

AC:

AN:

44556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

85782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52796

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111492

Other (OTH)

AF:

0.0000166

AC:

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000177

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000651

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000847

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4551998:Brain small vessel disease 1 with or without ocular anomalies;C5231411:Microangiopathy and leukoencephalopathy, pontine, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.40

MetaSVM

Uncertain

0.66

MutationAssessor

Benign

1.5

PhyloP100

7.3

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.65

Sift

Benign

0.23

Sift4G

Benign

0.15

Polyphen

0.99

Vest4

0.48

MVP

0.72

MPC

0.41

ClinPred

0.10

GERP RS

4.7

Varity_R

0.15

gMVP

0.75

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.046

dbscSNV1_RF

Benign

0.40

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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