rs144586397

chrX-108581000-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_033380.3(COL4A5):c.909T>C(p.Asp303=) 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:5
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 504907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108581000-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.909T>C	p.Asp303=	synonymous_variant	16/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.909T>C	p.Asp303=	synonymous_variant	16/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.909T>C	p.Asp303=	synonymous_variant	16/51	2		P1

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 139 AN: 111485 Hom.: 3 Cov.: 22 AF XY: 0.00122 AC XY: 41 AN XY: 33679

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

GnomAD3 exomes AF: 0.00379 AC: 694 AN: 183338 Hom.: 8 AF XY: 0.00251 AC XY: 170 AN XY: 67818

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000167

Gnomad4 OTH exome AF: 0.000522

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

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000660

Alfa AF: 0.00139 Hom.: 9

Bravo AF: 0.00229

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 19, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2016

p.Asp303Asp in exon 16 of COL4A5: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 2.64% (245/9283) o f Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs144586397). -

X-linked Alport syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	7.9
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs144586397; hg19: chrX-107824230;