rs34004222

Variant names:

• chr13-110213999-G-A
• rs34004222
• NM_001845.6:c.161C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001845.6(COL4A1):​c.161C>T​(p.Pro54Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00395 in 1,613,946 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P54S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (21 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 4.87
• Publications: 10 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: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, 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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001845.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.012423754).
• BP6: Variant 13-110213999-G-A is Benign according to our data. Variant chr13-110213999-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196327.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00264 (401/152100) while in subpopulation NFE AF = 0.00407 (277/68008). AF 95% confidence interval is 0.00368. There are 1 homozygotes in GnomAd4. There are 205 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.161C>T	p.Pro54Leu	missense_variant	Exon 3 of 52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.161C>T	p.Pro54Leu	missense_variant	Exon 3 of 25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.161C>T	p.Pro54Leu	missense_variant	Exon 3 of 52	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 401 AN: 151982 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000871

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00539

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00292 AC: 735 AN: 251454 AF XY: 0.00291

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00408 AC: 5970 AN: 1461846 Hom.: 21 Cov.: 33 AF XY: 0.00410 AC XY: 2983 AN XY: 727224

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000693 AC: 31 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86256

European-Finnish (FIN) AF: 0.00681 AC: 364 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00468 AC: 5206 AN: 1111972

Other (OTH) AF: 0.00243 AC: 147 AN: 60390

GnomAD4 genome AF: 0.00264 AC: 401 AN: 152100 Hom.: 1 Cov.: 32 AF XY: 0.00276 AC XY: 205 AN XY: 74344

African (AFR) AF: 0.000868 AC: 36 AN: 41474

American (AMR) AF: 0.00105 AC: 16 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00539 AC: 57 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 68008

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.00236

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Mar 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 32172663, 32040484, 30653986, 30467950, 29507195) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL4A1: BS1, BS2 -

Aug 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Oct 21, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Brain small vessel disease 1 with or without ocular anomalies Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Chronic kidney disease Uncertain:1

May 28, 2020

Cavalleri Lab, Royal College of Surgeons in Ireland

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PP2, PP3, BP6 -

Optic nerve hypoplasia Uncertain:1

-

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

COL4A1-related disorder Benign:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.5	L;L
PhyloP100		4.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.42	T;T
Polyphen		1.0	D;.
Vest4		0.54
MVP		0.86
MPC		0.39
ClinPred		0.011	T
GERP RS		5.0
Varity_R		0.48
gMVP		0.72
Mutation Taster		=51/49	polymorphism

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: rs34004222; hg19: chr13-110866346;