rs73251797

Positions:

• chrX-108159454-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033641.4(COL4A6):​c.4812+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0466 in 1,209,962 control chromosomes in the GnomAD database, including 993 homozygotes. There are 18,294 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (126 hom., 1661 hem., cov: 23)
  • Exomes 𝑓: 0.046 (867 hom. 16633 hem.)
• Consequence: COL4A6 NM_033641.4 splice_region, intron
• Scores: Splicing: ADA: 0.00009680
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.220

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-108159454-G-A is Benign according to our data. Variant chrX-108159454-G-A is described in ClinVar as [Benign]. Clinvar id is 258280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.086 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.4812+8C>T		splice_region_variant, intron_variant		ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.4812+8C>T		splice_region_variant, intron_variant		5	NM_033641.4	ENSP00000334733	P4

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 5729 AN: 112291 Hom.: 126 Cov.: 23 AF XY: 0.0481 AC XY: 1656 AN XY: 34443

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.0425

Gnomad ASJ AF: 0.0385

Gnomad EAS AF: 0.0944

Gnomad SAS AF: 0.0384

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0549

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0502 AC: 9074 AN: 180829 Hom.: 174 AF XY: 0.0477 AC XY: 3150 AN XY: 66099

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.0380

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0484

Gnomad OTH exome AF: 0.0524

GnomAD4 exome AF: 0.0461 AC: 50593 AN: 1097619 Hom.: 867 Cov.: 31 AF XY: 0.0458 AC XY: 16633 AN XY: 363023

Gnomad4 AFR exome AF: 0.0560

Gnomad4 AMR exome AF: 0.0455

Gnomad4 ASJ exome AF: 0.0407

Gnomad4 EAS exome AF: 0.0715

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0376

Gnomad4 NFE exome AF: 0.0455

Gnomad4 OTH exome AF: 0.0494

GnomAD4 genome AF: 0.0511 AC: 5736 AN: 112343 Hom.: 126 Cov.: 23 AF XY: 0.0481 AC XY: 1661 AN XY: 34505

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.0425

Gnomad4 ASJ AF: 0.0385

Gnomad4 EAS AF: 0.0944

Gnomad4 SAS AF: 0.0386

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0485

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0501 Hom.: 508

Bravo AF: 0.0530

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Hearing loss, X-linked 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.010		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: rs73251797; hg19: chrX-107402684;