chrX-108440158-C-T

Variant names:

• chrX-108440158-C-T
• rs773115274
• NM_033380.3:c.33C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_033380.3(COL4A5):​c.33C>T​(p.Gly11Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,205,591 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 3 hem., cov: 20)
  • Exomes 𝑓: 0.00013 (0 hom. 44 hem.)
• Consequence: COL4A5 NM_033380.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.31
• Publications: 0 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: ClinGen, G2P
• X-linked Alport syndrome

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-108440158-C-T is Benign according to our data. Variant chrX-108440158-C-T is described in ClinVar as [Benign]. Clinvar id is 1967561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.32 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A5	NM_033380.3	c.33C>T	p.Gly11Gly	synonymous_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.33C>T	p.Gly11Gly	synonymous_variant	Exon 1 of 51		NP_000486.1
COL4A5	XM_047441811.1	c.33C>T	p.Gly11Gly	synonymous_variant	Exon 1 of 42		XP_047297767.1
COL4A5	XM_047441810.1	c.-344C>T		5_prime_UTR_variant	Exon 1 of 54		XP_047297766.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A5	ENST00000328300.11	c.33C>T	p.Gly11Gly	synonymous_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes AF: 0.0000826 AC: 9 AN: 108931 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000986

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: 0.000114

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000772 AC: 14 AN: 181428 AF XY: 0.0000604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000129 AC: 142 AN: 1096660 Hom.: 0 Cov.: 29 AF XY: 0.000122 AC XY: 44 AN XY: 362070

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.0000852 AC: 3 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.00 AC: 0 AN: 54021

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.000164 AC: 138 AN: 841145

Other (OTH) AF: 0.0000217 AC: 1 AN: 46033

GnomAD4 genome AF: 0.0000826 AC: 9 AN: 108931 Hom.: 0 Cov.: 20 AF XY: 0.0000962 AC XY: 3 AN XY: 31197

African (AFR) AF: 0.0000671 AC: 2 AN: 29798

American (AMR) AF: 0.0000986 AC: 1 AN: 10137

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2600

East Asian (EAS) AF: 0.00 AC: 0 AN: 3438

South Asian (SAS) AF: 0.00 AC: 0 AN: 2429

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.000114 AC: 6 AN: 52566

Other (OTH) AF: 0.00 AC: 0 AN: 1450

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.000109

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		3.3
PromoterAI		0.012	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs773115274; hg19: chrX-107683388;