rs751749989

chr13-110307021-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001845.6(COL4A1):c.7C>A(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,464,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. P3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 2.70

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]

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL4A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.07972333).
• BP6: Variant 13-110307021-G-T is Benign according to our data. Variant chr13-110307021-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, Benign=1}. Variant chr13-110307021-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00044 (67/152198) while in subpopulation NFE AF= 0.00078 (53/67980). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.7C>A	p.Pro3Thr	missense_variant	1/52	ENST00000375820.10
COL4A1	NM_001303110.2	c.7C>A	p.Pro3Thr	missense_variant	1/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.7C>A	p.Pro3Thr	missense_variant	1/52	1	NM_001845.6	P1
COL4A1	ENST00000543140.6	c.7C>A	p.Pro3Thr	missense_variant	1/25	1
COL4A2	ENST00000400163.7	c.-44-839G>T		intron_variant		5
COL4A1	ENST00000649738.1	n.137C>A		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000780

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000587 AC: 47 AN: 80102 Hom.: 0 AF XY: 0.000568 AC XY: 26 AN XY: 45798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000538

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000434

GnomAD4 exome AF: 0.000689 AC: 904 AN: 1312428 Hom.: 1 Cov.: 33 AF XY: 0.000675 AC XY: 436 AN XY: 646298

Gnomad4 AFR exome AF: 0.000188

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000630

Gnomad4 FIN exome AF: 0.00237

Gnomad4 NFE exome AF: 0.000718

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74402

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.000780

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000794 Hom.: 0

Bravo AF: 0.000536

ExAC AF: 0.000227 AC: 5

Asia WGS AF: 0.000580 AC: 2 AN: 3464

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2023	Reported in an individual with pediatric arterial ischemic stroke in published literature (Grossi et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar (ClinVar Variant ID# 289628); This variant is associated with the following publications: (PMID: 32818659) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	COL4A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Mar 26, 2019	This variant was classified as: Likely benign. The following ACMG criteria were applied in classifying this variant: BS1,BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 03, 2017	- -

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

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital

Mar 26, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.60	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.097	T;T
Polyphen		0.043	B;.
Vest4		0.19
MVP		0.60
MPC		0.43
ClinPred		0.057	T
GERP RS		1.6
Varity_R		0.092
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs751749989; hg19: chr13-110959368;