rs144586397

Variant names:

• chrX-108581000-T-C
• rs144586397
• NM_033380.3:c.909T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033380.3(COL4A5):​c.909T>C​(p.Asp303Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,207,337 control chromosomes in the GnomAD database, including 17 homozygotes. There are 255 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., 41 hem., cov: 22)
  • Exomes 𝑓: 0.00080 (14 hom. 214 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.15
• 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: G2P, ClinGen
• X-linked Alport syndrome

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-108581000-T-C is Benign according to our data. Variant chrX-108581000-T-C is described in ClinVar as Benign. ClinVar VariationId is 504907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00125 (139/111536) while in subpopulation AMR AF = 0.0129 (134/10426). AF 95% confidence interval is 0.0111. There are 3 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	NM_033380.3	MANE Select	c.909T>C	p.Asp303Asp	synonymous	Exon 16 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.909T>C	p.Asp303Asp	synonymous	Exon 16 of 51	NP_000486.1	P29400-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A5	ENST00000328300.11	TSL:1 MANE Select	c.909T>C	p.Asp303Asp	synonymous	Exon 16 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.909T>C	p.Asp303Asp	synonymous	Exon 16 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.909T>C	p.Asp303Asp	synonymous	Exon 16 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 139 AN: 111485 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000668

GnomAD2 exomes AF: 0.00379 AC: 694 AN: 183338 AF XY: 0.00251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0250

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000801 AC: 878 AN: 1095801 Hom.: 14 Cov.: 29 AF XY: 0.000592 AC XY: 214 AN XY: 361365

African (AFR) AF: 0.00 AC: 0 AN: 26346

American (AMR) AF: 0.0239 AC: 840 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 54090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.0000167 AC: 14 AN: 839966

Other (OTH) AF: 0.000522 AC: 24 AN: 46008

GnomAD4 genome AF: 0.00125 AC: 139 AN: 111536 Hom.: 3 Cov.: 22 AF XY: 0.00122 AC XY: 41 AN XY: 33740

African (AFR) AF: 0.000130 AC: 4 AN: 30709

American (AMR) AF: 0.0129 AC: 134 AN: 10426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2661

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6007

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53112

Other (OTH) AF: 0.000660 AC: 1 AN: 1516

Alfa AF: 0.00139 Hom.: 9

Bravo AF: 0.00229

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	X-linked Alport syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.9
DANN	Benign	0.61
PhyloP100		3.1
Mutation Taster		=91/9	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: rs144586397; hg19: chrX-107824230;