rs61746140

Variant names:

• chrX-108686107-C-T
• rs61746140
• NM_033380.3:c.4293C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_033380.3(COL4A5):​c.4293C>T​(p.Asp1431Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,207,264 control chromosomes in the GnomAD database, including 2,328 homozygotes. There are 7,010 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (1150 hom., 2807 hem., cov: 23)
  • Exomes 𝑓: 0.014 (1178 hom. 4203 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0940
• Publications: 3 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 (REVEL=0.142).
• BP6: Variant X-108686107-C-T is Benign according to our data. Variant chrX-108686107-C-T is described in ClinVar as Benign. ClinVar VariationId is 24722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.094 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.309 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.4293C>T	p.Asp1431Asp	synonymous	Exon 48 of 53	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.4275C>T	p.Asp1425Asp	synonymous	Exon 46 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.4293C>T	p.Asp1431Asp	synonymous	Exon 48 of 53	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.4287C>T	p.Asp1429Asp	synonymous	Exon 46 of 51	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.4275C>T	p.Asp1425Asp	synonymous	Exon 46 of 51	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.0952 AC: 10543 AN: 110723 Hom.: 1150 Cov.: 23

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.00305

Gnomad EAS AF: 0.0765

Gnomad SAS AF: 0.0134

Gnomad FIN AF: 0.000167

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.0779

GnomAD2 exomes AF: 0.0367 AC: 6680 AN: 181933 AF XY: 0.0256

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.0406

Gnomad ASJ exome AF: 0.00375

Gnomad EAS exome AF: 0.0773

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000702

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0136 AC: 14923 AN: 1096486 Hom.: 1178 Cov.: 29 AF XY: 0.0116 AC XY: 4203 AN XY: 361958

African (AFR) AF: 0.322 AC: 8479 AN: 26348

American (AMR) AF: 0.0442 AC: 1554 AN: 35120

Ashkenazi Jewish (ASJ) AF: 0.00361 AC: 70 AN: 19369

East Asian (EAS) AF: 0.0806 AC: 2432 AN: 30157

South Asian (SAS) AF: 0.00948 AC: 512 AN: 54000

European-Finnish (FIN) AF: 0.000124 AC: 5 AN: 40477

Middle Eastern (MID) AF: 0.0106 AC: 43 AN: 4062

European-Non Finnish (NFE) AF: 0.000511 AC: 430 AN: 840915

Other (OTH) AF: 0.0304 AC: 1398 AN: 46038

GnomAD4 genome AF: 0.0952 AC: 10547 AN: 110778 Hom.: 1150 Cov.: 23 AF XY: 0.0850 AC XY: 2807 AN XY: 33042

African (AFR) AF: 0.315 AC: 9515 AN: 30246

American (AMR) AF: 0.0527 AC: 549 AN: 10426

Ashkenazi Jewish (ASJ) AF: 0.00305 AC: 8 AN: 2625

East Asian (EAS) AF: 0.0764 AC: 267 AN: 3495

South Asian (SAS) AF: 0.0130 AC: 34 AN: 2611

European-Finnish (FIN) AF: 0.000167 AC: 1 AN: 5978

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

European-Non Finnish (NFE) AF: 0.00108 AC: 57 AN: 52991

Other (OTH) AF: 0.0769 AC: 116 AN: 1509

Alfa AF: 0.0335 Hom.: 1910

Bravo AF: 0.111

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	5.9
DANN	Benign	0.58
PhyloP100		-0.094
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs61746140; hg19: chrX-107929337; COSMIC: COSV60360600;