rs145172612

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP6BS1BS2

The NM_001845.6(COL4A1):c.1588C>T(p.Pro530Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000362 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5

Conservation

PhyloP100: 7.29

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL4A1. . Gene score misZ 3.0194 (greater than the threshold 3.09). Trascript score misZ 4.972 (greater than threshold 3.09). GenCC has associacion of gene with brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.

BP6

Variant 13-110187278-G-A is Benign according to our data. Variant chr13-110187278-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195868.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00027 (41/152064) while in subpopulation NFE AF= 0.000544 (37/68008). AF 95% confidence interval is 0.000405. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6 linkuse as main transcript	c.1588C>T	p.Pro530Ser	missense_variant	25/52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.1588C>T	p.Pro530Ser	missense_variant	25/52	1	NM_001845.6	ENSP00000364979	P1	P02462-1
COL4A1	ENST00000649738.1 linkuse as main transcript	n.1718C>T		non_coding_transcript_exon_variant	25/31

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000544

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000390

AC:

AN:

251226

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000749

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000372

AC:

543

AN:

1461138

Hom.:

Cov.:

AF XY:

0.000391

AC XY:

284

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000445

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000270

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000646

Hom.:

Bravo

AF:

0.000287

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000830

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The COL4A1 p.Pro530Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs145172612), ClinVar (classified as a VUS by EGL Genetics, Illumina Clinical Services and Fulgent Genetics) and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 107 of 282602 chromosomes (1 homozygous) at a frequency of 0.000379 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: European (non-Finnish) in 94 of 128944 chromosomes (freq: 0.000729), Other in 5 of 7212 chromosomes (freq: 0.000693), Latino in 6 of 35428 chromosomes (freq: 0.000169), African in 1 of 24958 chromosomes (freq: 0.00004) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro530 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	COL4A1: BS1 -

COL4A1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The COL4A1 c.1588C>T variant is predicted to result in the amino acid substitution p.Pro530Ser. This variant was reported in members from one family who are affected with Marfan syndrome and was classified as variant of uncertain significance (Aubart et al. 2018. PubMed ID: 30087447) and has been reported in a patient with a renal ciliopathy syndrome (Al Alawi I et al 2021. PubMed ID: 34354814). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD including one homozygous individual. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Schizencephaly;C0423401: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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Porencephalic cyst

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.69

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.80

Sift

Benign

0.032

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.68

MVP

0.79

MPC

0.39

ClinPred

0.10

GERP RS

4.7

Varity_R

0.39

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over