rs16975424

Variant names:

• chr13-110162576-A-G
• rs16975424
• NM_001845.6:c.4250-134T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.4250-134T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 733,940 control chromosomes in the GnomAD database, including 8,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1375 hom., cov: 33)
  • Exomes 𝑓: 0.15 (7273 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.303
• 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: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-110162576-A-G is Benign according to our data. Variant chr13-110162576-A-G is described in ClinVar as Benign. ClinVar VariationId is 1292897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.4250-134T>C		intron	N/A	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4250-134T>C		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000650424.2		c.4250-134T>C		intron	N/A	ENSP00000497477.2
	COL4A1	ENST00000615732.3	TSL:5	c.4058-134T>C		intron	N/A	ENSP00000478222.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18731 AN: 152106 Hom.: 1379 Cov.: 33

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.155

GnomAD4 exome AF: 0.153 AC: 89015 AN: 581716 Hom.: 7273 AF XY: 0.154 AC XY: 47747 AN XY: 310098

African (AFR) AF: 0.0409 AC: 610 AN: 14908

American (AMR) AF: 0.140 AC: 3696 AN: 26416

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 2963 AN: 17802

East Asian (EAS) AF: 0.186 AC: 5989 AN: 32234

South Asian (SAS) AF: 0.171 AC: 9572 AN: 56038

European-Finnish (FIN) AF: 0.112 AC: 3816 AN: 33970

Middle Eastern (MID) AF: 0.207 AC: 486 AN: 2352

European-Non Finnish (NFE) AF: 0.155 AC: 56999 AN: 367088

Other (OTH) AF: 0.158 AC: 4884 AN: 30908

GnomAD4 genome AF: 0.123 AC: 18717 AN: 152224 Hom.: 1375 Cov.: 33 AF XY: 0.124 AC XY: 9208 AN XY: 74428

African (AFR) AF: 0.0395 AC: 1640 AN: 41558

American (AMR) AF: 0.154 AC: 2361 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3470

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5174

South Asian (SAS) AF: 0.184 AC: 887 AN: 4824

European-Finnish (FIN) AF: 0.103 AC: 1092 AN: 10588

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10631 AN: 68002

Other (OTH) AF: 0.154 AC: 326 AN: 2114

Alfa AF: 0.132 Hom.: 175

Bravo AF: 0.122

Asia WGS AF: 0.206 AC: 716 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.68
PhyloP100		-0.30
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: rs16975424; hg19: chr13-110814923;