X-108440157-G-T

Variant names:

• chrX-108440157-G-T
• rs769068931
• NM_033380.3:c.32G>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_033380.3(COL4A5):​c.32G>T​(p.Gly11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,205,867 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000083 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00013 (0 hom. 44 hem.)
• Consequence: COL4A5 NM_033380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38764292).
• 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.32G>T	p.Gly11Val	missense_variant	Exon 1 of 53	ENST00000328300.11	NP_203699.1
COL4A5	NM_000495.5	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 51		NP_000486.1
COL4A5	XM_047441811.1	c.32G>T	p.Gly11Val	missense_variant	Exon 1 of 42		XP_047297767.1
COL4A5	XM_047441810.1	c.-345G>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.32G>T	p.Gly11Val	missense_variant	Exon 1 of 53	1	NM_033380.3	ENSP00000331902.7

Frequencies

GnomAD3 genomes AF: 0.0000826 AC: 9 AN: 108996 Hom.: 0 Cov.: 21 AF XY: 0.0000959 AC XY: 3 AN XY: 31270

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000987

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

GnomAD3 exomes AF: 0.0000771 AC: 14 AN: 181467 Hom.: 0 AF XY: 0.0000604 AC XY: 4 AN XY: 66201

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 SAS 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: 1096871 Hom.: 0 Cov.: 29 AF XY: 0.000121 AC XY: 44 AN XY: 362303

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000852

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: 0.000164

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000826 AC: 9 AN: 108996 Hom.: 0 Cov.: 21 AF XY: 0.0000959 AC XY: 3 AN XY: 31270

Gnomad4 AFR AF: 0.0000671

Gnomad4 AMR AF: 0.0000987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000114

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32G>T (p.G11V) alteration is located in exon 1 (coding exon 1) of the COL4A5 gene. This alteration results from a G to T substitution at nucleotide position 32, causing the glycine (G) at amino acid position 11 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	.;T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.59	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.55	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.80	.;P
Vest4		0.45
MutPred		0.47		Loss of MoRF binding (P = 0.1336);Loss of MoRF binding (P = 0.1336);
MVP		0.94
MPC		0.37
ClinPred		0.074	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.72

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: rs769068931; hg19: chrX-107683387;