rs143020337

chrX-108680941-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_033380.3(COL4A5):c.4072C>A(p.Leu1358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,204,879 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 69 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00019 (0 hom. 66 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.838

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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_033380.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0934529).
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A5	NM_033380.3	c.4072C>A	p.Leu1358Ile	missense_variant	46/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.4072C>A	p.Leu1358Ile	missense_variant	46/53	1	NM_033380.3
COL4A5	ENST00000361603.7	c.4054C>A	p.Leu1352Ile	missense_variant	44/51	2		P1
COL4A5	ENST00000489230.1	n.475C>A		non_coding_transcript_exon_variant	5/8	5
COL4A5	ENST00000510690.2	n.566C>A		non_coding_transcript_exon_variant	4/11	4

Frequencies

GnomAD3 genomes AF: 0.000108 AC: 12 AN: 111471 Hom.: 0 Cov.: 22 AF XY: 0.0000892 AC XY: 3 AN XY: 33647

Gnomad AFR AF: 0.0000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 24 AN: 183054 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000294

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000194 AC: 212 AN: 1093355 Hom.: 0 Cov.: 30 AF XY: 0.000184 AC XY: 66 AN XY: 358927

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.000249

Gnomad4 OTH exome AF: 0.0000653

GnomAD4 genome AF: 0.000108 AC: 12 AN: 111524 Hom.: 0 Cov.: 22 AF XY: 0.0000890 AC XY: 3 AN XY: 33710

Gnomad4 AFR AF: 0.0000651

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000978 Hom.: 0

Bravo AF: 0.000125

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	See Variant Classification Assertion Criteria. -

Alport syndrome Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	15
Dann	Benign	0.95
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-0.31	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.31	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.43	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.046	.;B
Vest4		0.29
MVP		0.80
MPC		0.53
ClinPred		0.057	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.050

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: rs143020337; hg19: chrX-107924171;