X-108157028-C-T

Variant names:

• chrX-108157028-C-T
• rs1282722908
• NM_033641.4:c.5045G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_033641.4(COL4A6):​c.5045G>A​(p.Arg1682His) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,097,782 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: COL4A6 NM_033641.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

Genes affected

COL4A6 (HGNC:2208): (collagen type IV alpha 6 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. 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, alpha 5 type IV collagen, so that the gene pair shares a common promoter. Deletions in the alpha 5 gene that extend into the alpha 6 gene result in diffuse leiomyomatosis accompanying the X-linked Alport syndrome caused by the deletion in the alpha 5 gene. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.5045G>A	p.Arg1682His	missense_variant	Exon 45 of 45	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.5045G>A	p.Arg1682His	missense_variant	Exon 45 of 45	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000548 AC: 1 AN: 182488 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67028

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097782 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 363194

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: 0.0000555

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000950

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5048G>A (p.R1683H) alteration is located in exon 45 (coding exon 45) of the COL4A6 gene. This alteration results from a G to A substitution at nucleotide position 5048, causing the arginine (R) at amino acid position 1683 to be replaced by a histidine (H). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.75
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;D;.;.;D;D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D;D;.;D;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.59
MutPred		0.81		.;Loss of MoRF binding (P = 0.007);.;.;.;.;
MVP		1.0
MPC		0.22
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.83
gMVP		0.95

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: rs1282722908; hg19: chrX-107400258; COSMIC: COSV57860094; COSMIC: COSV57860094;