rs190579028

Variant names:

• chrX-108626199-A-T
• rs190579028
• NM_033380.3:c.3107-11A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033380.3(COL4A5):​c.3107-11A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,203,954 control chromosomes in the GnomAD database, including 1 homozygotes. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00015 (1 hom. 58 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Scores: Splicing: ADA: 0.00002480
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.191
• Publications: 1 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=-0.83).
• BP6: Variant X-108626199-A-T is Benign according to our data. Variant chrX-108626199-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000216 (24/111134) while in subpopulation EAS AF = 0.00628 (22/3504). AF 95% confidence interval is 0.00425. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.3107-11A>T		intron	N/A	NP_203699.1
	COL4A5	NM_000495.5		c.3107-11A>T		intron	N/A	NP_000486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.3107-11A>T		intron	N/A	ENSP00000331902.7
	COL4A5	ENST00000483338.1	TSL:1	c.1931-11A>T		intron	N/A	ENSP00000495685.1
	COL4A5	ENST00000361603.7	TSL:2	c.3107-11A>T		intron	N/A	ENSP00000354505.2

Frequencies

GnomAD3 genomes AF: 0.000216 AC: 24 AN: 111087 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00626

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00136

GnomAD2 exomes AF: 0.000367 AC: 67 AN: 182438 AF XY: 0.000327

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00472

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000155 AC: 169 AN: 1092820 Hom.: 1 Cov.: 29 AF XY: 0.000162 AC XY: 58 AN XY: 358952

African (AFR) AF: 0.00 AC: 0 AN: 26282

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00518 AC: 156 AN: 30143

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53999

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3676

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 837900

Other (OTH) AF: 0.000218 AC: 10 AN: 45872

GnomAD4 genome AF: 0.000216 AC: 24 AN: 111134 Hom.: 0 Cov.: 23 AF XY: 0.000240 AC XY: 8 AN XY: 33352

African (AFR) AF: 0.00 AC: 0 AN: 30572

American (AMR) AF: 0.00 AC: 0 AN: 10403

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00628 AC: 22 AN: 3504

South Asian (SAS) AF: 0.00 AC: 0 AN: 2593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5983

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53042

Other (OTH) AF: 0.00134 AC: 2 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.68
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.018
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: rs190579028; hg19: chrX-107869429;