NM_001845.6:c.781-79dupT

Variant names:

• chr13-110206969-G-GA
• rs60585275
• NM_001845.6:c.781-79dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001845.6(COL4A1):​c.781-79dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,039,802 control chromosomes in the GnomAD database, including 32 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 18)
  • Exomes 𝑓: 0.12 (5 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.896
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 13-110206969-G-GA is Benign according to our data. Variant chr13-110206969-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 1196465.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1751/139974) while in subpopulation AFR AF = 0.0385 (1462/37976). AF 95% confidence interval is 0.0369. There are 27 homozygotes in GnomAd4. There are 822 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.781-79dupT		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.781-79dupT		intron	N/A	NP_001290039.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.781-79_781-78insT		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.781-79_781-78insT		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.781-79_781-78insT		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1741 AN: 139914 Hom.: 26 Cov.: 18

Gnomad AFR AF: 0.0383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00237

Gnomad SAS AF: 0.000454

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.119 AC: 107049 AN: 899828 Hom.: 5 AF XY: 0.120 AC XY: 54511 AN XY: 453642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.159 AC: 3096 AN: 19518

American (AMR) AF: 0.0873 AC: 2161 AN: 24760

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 2497 AN: 16520

East Asian (EAS) AF: 0.269 AC: 5677 AN: 21068

South Asian (SAS) AF: 0.143 AC: 7562 AN: 52770

European-Finnish (FIN) AF: 0.0872 AC: 3384 AN: 38806

Middle Eastern (MID) AF: 0.0935 AC: 368 AN: 3934

European-Non Finnish (NFE) AF: 0.113 AC: 77330 AN: 684776

Other (OTH) AF: 0.132 AC: 4974 AN: 37676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0125 AC: 1751 AN: 139974 Hom.: 27 Cov.: 18 AF XY: 0.0121 AC XY: 822 AN XY: 67862

African (AFR) AF: 0.0385 AC: 1462 AN: 37976

American (AMR) AF: 0.00609 AC: 86 AN: 14116

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 39 AN: 3300

East Asian (EAS) AF: 0.00238 AC: 11 AN: 4622

South Asian (SAS) AF: 0.000456 AC: 2 AN: 4390

European-Finnish (FIN) AF: 0.00329 AC: 29 AN: 8812

Middle Eastern (MID) AF: 0.00725 AC: 2 AN: 276

European-Non Finnish (NFE) AF: 0.00141 AC: 90 AN: 63722

Other (OTH) AF: 0.0157 AC: 30 AN: 1912

Alfa AF: 0.00 Hom.: 313

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs60585275; hg19: chr13-110859316; COSMIC: COSV65425209;