13-110166251-T-G

Variant names:

• chr13-110166251-T-G
• rs3742207
• NM_001845.6:c.4002A>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.4002A>C​(p.Gln1334His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,606,430 control chromosomes in the GnomAD database, including 88,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1334R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.31 (7518 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80761 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.718
• Publications: 77 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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 3 uncertain in NM_001845.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.013116002).
• BP6: Variant 13-110166251-T-G is Benign according to our data. Variant chr13-110166251-T-G is described in ClinVar as Benign. ClinVar VariationId is 197520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 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.4002A>C	p.Gln1334His	missense	Exon 45 of 52	NP_001836.3	P02462-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4002A>C	p.Gln1334His	missense	Exon 45 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.4002A>C	p.Gln1334His	missense	Exon 45 of 52	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.3903A>C	p.Gln1301His	missense	Exon 44 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47236 AN: 151996 Hom.: 7517 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.343

Gnomad OTH AF: 0.337

GnomAD2 exomes AF: 0.304 AC: 76506 AN: 251484 AF XY: 0.313

Gnomad AFR exome AF: 0.284

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.330 AC: 479380 AN: 1454316 Hom.: 80761 Cov.: 30 AF XY: 0.331 AC XY: 239763 AN XY: 724036

African (AFR) AF: 0.280 AC: 9335 AN: 33340

American (AMR) AF: 0.193 AC: 8618 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10205 AN: 26102

East Asian (EAS) AF: 0.257 AC: 10196 AN: 39670

South Asian (SAS) AF: 0.334 AC: 28745 AN: 86130

European-Finnish (FIN) AF: 0.266 AC: 14181 AN: 53406

Middle Eastern (MID) AF: 0.403 AC: 2316 AN: 5748

European-Non Finnish (NFE) AF: 0.340 AC: 376253 AN: 1105030

Other (OTH) AF: 0.325 AC: 19531 AN: 60176

GnomAD4 genome AF: 0.311 AC: 47251 AN: 152114 Hom.: 7518 Cov.: 32 AF XY: 0.306 AC XY: 22776 AN XY: 74360

African (AFR) AF: 0.280 AC: 11596 AN: 41466

American (AMR) AF: 0.264 AC: 4036 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1386 AN: 3470

East Asian (EAS) AF: 0.239 AC: 1238 AN: 5176

South Asian (SAS) AF: 0.313 AC: 1509 AN: 4822

European-Finnish (FIN) AF: 0.268 AC: 2834 AN: 10590

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.343 AC: 23344 AN: 67996

Other (OTH) AF: 0.334 AC: 704 AN: 2110

Alfa AF: 0.330 Hom.: 42658

Bravo AF: 0.305

TwinsUK AF: 0.339 AC: 1256

ALSPAC AF: 0.342 AC: 1319

ESP6500AA AF: 0.282 AC: 1243

ESP6500EA AF: 0.341 AC: 2935

ExAC AF: 0.310 AC: 37612

Asia WGS AF: 0.259 AC: 901 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.355

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Brain small vessel disease 1 with or without ocular anomalies (3)
-	-	2	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)
-	-	2	not provided (2)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.72
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.26	B
Vest4		0.055
MutPred		0.25		Gain of catalytic residue at D1330 (P = 0)
MPC		0.59
ClinPred		0.019	T
GERP RS		-1.2
Varity_R		0.067
gMVP		0.66
Mutation Taster		=92/8	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: rs3742207; hg19: chr13-110818598; COSMIC: COSV65421515; COSMIC: COSV65421515;