rs1778817

Positions:

• chr13-110167113-G-A
• chr13-110167113-G-T

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.3949+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,531,910 control chromosomes in the GnomAD database, including 326,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29517 hom., cov: 31)
  • Exomes 𝑓: 0.66 (297455 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.32

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 13-110167113-G-A is Benign according to our data. Variant chr13-110167113-G-A is described in ClinVar as [Benign]. Clinvar id is 1260831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110167113-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3949+45C>T		intron_variant		ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3949+45C>T		intron_variant		1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000650424.1	c.103+45C>T		intron_variant				ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.620 AC: 93859 AN: 151390 Hom.: 29512 Cov.: 31

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.606

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.610

GnomAD3 exomes AF: 0.659 AC: 165593 AN: 251232 Hom.: 55076 AF XY: 0.659 AC XY: 89509 AN XY: 135838

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.651

Gnomad SAS exome AF: 0.657

Gnomad FIN exome AF: 0.733

Gnomad NFE exome AF: 0.657

Gnomad OTH exome AF: 0.637

GnomAD4 exome AF: 0.655 AC: 904396 AN: 1380400 Hom.: 297455 Cov.: 22 AF XY: 0.655 AC XY: 453039 AN XY: 691556

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.715

Gnomad4 ASJ exome AF: 0.602

Gnomad4 EAS exome AF: 0.649

Gnomad4 SAS exome AF: 0.661

Gnomad4 FIN exome AF: 0.729

Gnomad4 NFE exome AF: 0.655

Gnomad4 OTH exome AF: 0.651

GnomAD4 genome AF: 0.620 AC: 93905 AN: 151510 Hom.: 29517 Cov.: 31 AF XY: 0.625 AC XY: 46292 AN XY: 74052

Gnomad4 AFR AF: 0.512

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.595

Gnomad4 EAS AF: 0.653

Gnomad4 SAS AF: 0.680

Gnomad4 FIN AF: 0.723

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.614

Alfa AF: 0.634 Hom.: 6459

Bravo AF: 0.613

Asia WGS AF: 0.690 AC: 2401 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.44
DANN	Benign	0.52

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: rs1778817; hg19: chr13-110819460;