rs117738194

Variant names:

• chr13-110170596-C-T
• rs117738194
• NM_001845.6:c.3693G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.3693G>A​(p.Thr1231Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,610,634 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (396 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.223
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 13-110170596-C-T is Benign according to our data. Variant chr13-110170596-C-T is described in ClinVar as Benign. ClinVar VariationId is 258252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0688 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.3693G>A	p.Thr1231Thr	synonymous	Exon 42 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.3693G>A	p.Thr1231Thr	synonymous	Exon 42 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000650424.2		c.3693G>A	p.Thr1231Thr	synonymous	Exon 42 of 52	ENSP00000497477.2	A0A3B3ISV3
	COL4A1	ENST00000933608.1		c.3594G>A	p.Thr1198Thr	synonymous	Exon 41 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1312 AN: 152246 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0221 AC: 5323 AN: 240386 AF XY: 0.0175

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00521

Gnomad EAS exome AF: 0.0822

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.00668 AC: 9743 AN: 1458270 Hom.: 396 Cov.: 32 AF XY: 0.00603 AC XY: 4374 AN XY: 725164

African (AFR) AF: 0.00123 AC: 41 AN: 33414

American (AMR) AF: 0.0978 AC: 4322 AN: 44172

Ashkenazi Jewish (ASJ) AF: 0.00527 AC: 137 AN: 25994

East Asian (EAS) AF: 0.0722 AC: 2865 AN: 39656

South Asian (SAS) AF: 0.00130 AC: 111 AN: 85600

European-Finnish (FIN) AF: 0.000188 AC: 10 AN: 53122

Middle Eastern (MID) AF: 0.00141 AC: 8 AN: 5684

European-Non Finnish (NFE) AF: 0.00157 AC: 1747 AN: 1110418

Other (OTH) AF: 0.00834 AC: 502 AN: 60210

GnomAD4 genome AF: 0.00868 AC: 1323 AN: 152364 Hom.: 49 Cov.: 33 AF XY: 0.00925 AC XY: 689 AN XY: 74508

African (AFR) AF: 0.00204 AC: 85 AN: 41594

American (AMR) AF: 0.0464 AC: 711 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.0749 AC: 388 AN: 5180

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 68034

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00375 Hom.: 4

Bravo AF: 0.0145

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Brain small vessel disease 1 with or without ocular anomalies (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.1
DANN	Benign	0.43
PhyloP100		0.22
Mutation Taster		=100/0	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: rs117738194; hg19: chr13-110822943; COSMIC: COSV107488281;