rs2272945

Variant names:

• chrX-108586677-G-C
• rs2272945
• NM_033380.3:c.1095G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-108586677-G-C
• chrX-108586677-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.1095G>C​(p.Gly365Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0245 in 1,205,928 control chromosomes in the GnomAD database, including 2,808 homozygotes. There are 8,319 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G365G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1347 hom., 3194 hem., cov: 22)
  • Exomes 𝑓: 0.016 (1461 hom. 5125 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.895
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant X-108586677-G-C is Benign according to our data. Variant chrX-108586677-G-C is described in ClinVar as Benign. ClinVar VariationId is 24365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.338 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.1095G>C	p.Gly365Gly	synonymous	Exon 19 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.1095G>C	p.Gly365Gly	synonymous	Exon 19 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.1095G>C	p.Gly365Gly	synonymous	Exon 19 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000483338.1	TSL:1	c.-82G>C		5_prime_UTR	Exon 3 of 20	ENSP00000495685.1	Q49AM6
	COL4A5	ENST00000949143.1		c.1095G>C	p.Gly365Gly	synonymous	Exon 19 of 51	ENSP00000619202.1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 11721 AN: 110336 Hom.: 1347 Cov.: 22

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.00304

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.0894

GnomAD2 exomes AF: 0.0458 AC: 8396 AN: 183258 AF XY: 0.0344

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.0437

Gnomad ASJ exome AF: 0.00374

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000843

Gnomad OTH exome AF: 0.0245

GnomAD4 exome AF: 0.0162 AC: 17771 AN: 1095540 Hom.: 1461 Cov.: 30 AF XY: 0.0142 AC XY: 5125 AN XY: 361180

African (AFR) AF: 0.346 AC: 9103 AN: 26327

American (AMR) AF: 0.0470 AC: 1654 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00362 AC: 70 AN: 19341

East Asian (EAS) AF: 0.124 AC: 3730 AN: 30185

South Asian (SAS) AF: 0.0151 AC: 816 AN: 54015

European-Finnish (FIN) AF: 0.000173 AC: 7 AN: 40526

Middle Eastern (MID) AF: 0.0119 AC: 49 AN: 4125

European-Non Finnish (NFE) AF: 0.000605 AC: 508 AN: 839867

Other (OTH) AF: 0.0399 AC: 1834 AN: 45989

GnomAD4 genome AF: 0.106 AC: 11733 AN: 110388 Hom.: 1347 Cov.: 22 AF XY: 0.0976 AC XY: 3194 AN XY: 32734

African (AFR) AF: 0.344 AC: 10381 AN: 30195

American (AMR) AF: 0.0560 AC: 582 AN: 10384

Ashkenazi Jewish (ASJ) AF: 0.00304 AC: 8 AN: 2635

East Asian (EAS) AF: 0.144 AC: 506 AN: 3502

South Asian (SAS) AF: 0.0208 AC: 54 AN: 2602

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5960

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

European-Non Finnish (NFE) AF: 0.00131 AC: 69 AN: 52712

Other (OTH) AF: 0.0883 AC: 132 AN: 1495

Alfa AF: 0.0156 Hom.: 102

Bravo AF: 0.123

EpiCase AF: 0.000928

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

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	-0.74
CADD	Benign	6.2
DANN	Benign	0.51
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2272945; hg19: chrX-107829907; COSMIC: COSV60358314;