NM_033380.3:c.2768-11A>G

Variant names:

• chrX-108622665-A-G
• rs1006269
• NM_033380.3:c.2768-11A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033380.3(COL4A5):​c.2768-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,207,751 control chromosomes in the GnomAD database, including 8,060 homozygotes. There are 50,294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (637 hom., 3543 hem., cov: 23)
  • Exomes 𝑓: 0.13 (7423 hom. 46751 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Scores: Splicing: ADA: 0.00003877
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.145
• Publications: 13 publications found

Genes affected

COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

COL4A5 Gene-Disease associations (from GenCC):

• Alport syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen, G2P
• X-linked Alport syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Genomics England PanelApp, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-108622665-A-G is Benign according to our data. Variant chrX-108622665-A-G is described in ClinVar as Benign. ClinVar VariationId is 24563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033380.3. 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
	COL4A5	NM_033380.3	MANE Select	c.2768-11A>G		intron	N/A	NP_203699.1
	COL4A5	NM_000495.5		c.2768-11A>G		intron	N/A	NP_000486.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.2768-11A>G		intron	N/A	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.1592-11A>G		intron	N/A	ENSP00000495685.1
	COL4A5	ENST00000949143.1		c.2780-11A>G		intron	N/A	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 11326 AN: 111943 Hom.: 638 Cov.: 23

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.0763

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.0696

Gnomad MID AF: 0.0763

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0979

GnomAD2 exomes AF: 0.161 AC: 29492 AN: 182713 AF XY: 0.159

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.323

Gnomad FIN exome AF: 0.0792

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.138

GnomAD4 exome AF: 0.126 AC: 138272 AN: 1095759 Hom.: 7423 Cov.: 30 AF XY: 0.129 AC XY: 46751 AN XY: 361757

African (AFR) AF: 0.0147 AC: 388 AN: 26354

American (AMR) AF: 0.313 AC: 11002 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1460 AN: 19361

East Asian (EAS) AF: 0.360 AC: 10879 AN: 30182

South Asian (SAS) AF: 0.246 AC: 13316 AN: 54068

European-Finnish (FIN) AF: 0.0819 AC: 3319 AN: 40514

Middle Eastern (MID) AF: 0.0665 AC: 262 AN: 3940

European-Non Finnish (NFE) AF: 0.110 AC: 92023 AN: 840200

Other (OTH) AF: 0.122 AC: 5623 AN: 45979

GnomAD4 genome AF: 0.101 AC: 11324 AN: 111992 Hom.: 637 Cov.: 23 AF XY: 0.104 AC XY: 3543 AN XY: 34190

African (AFR) AF: 0.0173 AC: 535 AN: 30953

American (AMR) AF: 0.222 AC: 2352 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 202 AN: 2647

East Asian (EAS) AF: 0.327 AC: 1145 AN: 3501

South Asian (SAS) AF: 0.236 AC: 630 AN: 2665

European-Finnish (FIN) AF: 0.0696 AC: 427 AN: 6132

Middle Eastern (MID) AF: 0.0698 AC: 15 AN: 215

European-Non Finnish (NFE) AF: 0.111 AC: 5869 AN: 53086

Other (OTH) AF: 0.0954 AC: 146 AN: 1531

Alfa AF: 0.111 Hom.: 5134

Bravo AF: 0.109

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	X-linked Alport syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.84
PhyloP100		-0.14
PromoterAI		0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0080
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: rs1006269; hg19: chrX-107865895; COSMIC: COSV60362795; COSMIC: COSV60362795;