chr13-110164956-G-A

Variant names:

• chr13-110164956-G-A
• rs140210015
• NM_001845.6:c.4056C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001845.6(COL4A1):​c.4056C>T​(p.Tyr1352Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,604,612 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.308
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-110164956-G-A is Benign according to our data. Variant chr13-110164956-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00292 (4237/1452398) while in subpopulation NFE AF = 0.00343 (3804/1108006). AF 95% confidence interval is 0.00334. There are 4 homozygotes in GnomAdExome4. There are 1984 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

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.4056C>T	p.Tyr1352Tyr	synonymous	Exon 46 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.4056C>T	p.Tyr1352Tyr	synonymous	Exon 46 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.4056C>T	p.Tyr1352Tyr	synonymous	Exon 46 of 52	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.3957C>T	p.Tyr1319Tyr	synonymous	Exon 45 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 287 AN: 152096 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00462

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00183 AC: 416 AN: 227572 AF XY: 0.00177

Gnomad AFR exome AF: 0.000571

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00432

Gnomad EAS exome AF: 0.0000595

Gnomad FIN exome AF: 0.0000504

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00292 AC: 4237 AN: 1452398 Hom.: 4 Cov.: 32 AF XY: 0.00275 AC XY: 1984 AN XY: 721542

African (AFR) AF: 0.000598 AC: 20 AN: 33430

American (AMR) AF: 0.00140 AC: 60 AN: 42858

Ashkenazi Jewish (ASJ) AF: 0.00399 AC: 103 AN: 25790

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39402

South Asian (SAS) AF: 0.000320 AC: 27 AN: 84284

European-Finnish (FIN) AF: 0.000227 AC: 12 AN: 52832

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 0.00343 AC: 3804 AN: 1108006

Other (OTH) AF: 0.00345 AC: 207 AN: 60058

GnomAD4 genome AF: 0.00189 AC: 287 AN: 152214 Hom.: 2 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74424

African (AFR) AF: 0.000554 AC: 23 AN: 41532

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00462 AC: 16 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00306 AC: 208 AN: 68002

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00212

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Brain small vessel disease 1 with or without ocular anomalies (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)
-	-	1	COL4A1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.19
PhyloP100		-0.31
Mutation Taster		=100/0	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: rs140210015; hg19: chr13-110817303; COSMIC: COSV101011190; COSMIC: COSV101011190;