NM_033380.3:c.3553+42T>C

Variant names:

• chrX-108666636-T-C
• rs28465565
• NM_033380.3:c.3553+42T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033380.3(COL4A5):​c.3553+42T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,064,300 control chromosomes in the GnomAD database, including 4,286 homozygotes. There are 8,964 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2234 hom., 4092 hem., cov: 23)
  • Exomes 𝑓: 0.019 (2052 hom. 4872 hem.)
• Consequence: COL4A5 NM_033380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.271
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-108666636-T-C is Benign according to our data. Variant chrX-108666636-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 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.3553+42T>C		intron	N/A	NP_203699.1	P29400-2
	COL4A5	NM_000495.5		c.3553+42T>C		intron	N/A	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.3553+42T>C		intron	N/A	ENSP00000331902.7	P29400-2
	COL4A5	ENST00000949143.1		c.3565+42T>C		intron	N/A	ENSP00000619202.1
	COL4A5	ENST00000361603.7	TSL:2	c.3553+42T>C		intron	N/A	ENSP00000354505.2	P29400-1

Frequencies

GnomAD3 genomes AF: 0.134 AC: 14925 AN: 111550 Hom.: 2233 Cov.: 23

Gnomad AFR AF: 0.441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0229

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0522 AC: 6224 AN: 119139 AF XY: 0.0399

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.0504

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.0312

GnomAD4 exome AF: 0.0193 AC: 18422 AN: 952695 Hom.: 2052 Cov.: 19 AF XY: 0.0185 AC XY: 4872 AN XY: 263657

African (AFR) AF: 0.448 AC: 10149 AN: 22671

American (AMR) AF: 0.0549 AC: 1569 AN: 28600

Ashkenazi Jewish (ASJ) AF: 0.00382 AC: 69 AN: 18067

East Asian (EAS) AF: 0.121 AC: 3277 AN: 27091

South Asian (SAS) AF: 0.0150 AC: 715 AN: 47674

European-Finnish (FIN) AF: 0.000184 AC: 7 AN: 38052

Middle Eastern (MID) AF: 0.0163 AC: 61 AN: 3746

European-Non Finnish (NFE) AF: 0.000767 AC: 557 AN: 725776

Other (OTH) AF: 0.0492 AC: 2018 AN: 41018

GnomAD4 genome AF: 0.134 AC: 14947 AN: 111605 Hom.: 2234 Cov.: 23 AF XY: 0.121 AC XY: 4092 AN XY: 33845

African (AFR) AF: 0.441 AC: 13425 AN: 30413

American (AMR) AF: 0.0662 AC: 699 AN: 10556

Ashkenazi Jewish (ASJ) AF: 0.00265 AC: 7 AN: 2644

East Asian (EAS) AF: 0.144 AC: 510 AN: 3541

South Asian (SAS) AF: 0.0223 AC: 60 AN: 2695

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00158 AC: 84 AN: 53239

Other (OTH) AF: 0.106 AC: 161 AN: 1514

Alfa AF: 0.0696 Hom.: 679

Bravo AF: 0.155

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.56
PhyloP100		-0.27
Mutation Taster		=100/0	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: rs28465565; hg19: chrX-107909866;