13-110198667-G-C

Position:

• chr13-110198667-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.1121-36C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,612,806 control chromosomes in the GnomAD database, including 106,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9157 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97724 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.622

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-110198667-G-C is Benign according to our data. Variant chr13-110198667-G-C is described in ClinVar as [Benign]. Clinvar id is 1262940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110198667-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1121-36C>G		intron_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1121-36C>G		intron_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1121-36C>G		intron_variant		1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000543140.6	c.1121-36C>G		intron_variant		1		ENSP00000443348.1
COL4A1	ENST00000647797.1	c.998-36C>G		intron_variant				ENSP00000497756.2
COL4A1	ENST00000649738.1	n.1251-36C>G		intron_variant

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52219 AN: 151966 Hom.: 9160 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.218

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.460

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.362 AC: 90357 AN: 249514 Hom.: 17193 AF XY: 0.371 AC XY: 50202 AN XY: 135180

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.450

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.362 AC: 528389 AN: 1460722 Hom.: 97724 Cov.: 39 AF XY: 0.365 AC XY: 265023 AN XY: 726682

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.511

Gnomad4 SAS exome AF: 0.445

Gnomad4 FIN exome AF: 0.348

Gnomad4 NFE exome AF: 0.354

Gnomad4 OTH exome AF: 0.376

GnomAD4 genome AF: 0.343 AC: 52229 AN: 152084 Hom.: 9157 Cov.: 32 AF XY: 0.346 AC XY: 25730 AN XY: 74322

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.372

Alfa AF: 0.294 Hom.: 1232

Bravo AF: 0.336

Asia WGS AF: 0.462 AC: 1605 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.49

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: rs496916; hg19: chr13-110851014; COSMIC: COSV65422868;