X-108172536-C-T

Position:

• chrX-108172536-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033641.4(COL4A6):​c.3139-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 1,194,948 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,223 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 0.0073 (9 hom., 234 hem., cov: 21)
  • Exomes 𝑓: 0.0086 (42 hom. 2989 hem.)
• Consequence: COL4A6 NM_033641.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002626
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.857

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant X-108172536-C-T is Benign according to our data. Variant chrX-108172536-C-T is described in ClinVar as [Benign]. Clinvar id is 258272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108172536-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A6	NM_033641.4	c.3139-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000334504.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A6	ENST00000334504.12	c.3139-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_033641.4	P4

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 800 AN: 109689 Hom.: 9 Cov.: 21 AF XY: 0.00732 AC XY: 234 AN XY: 31959

Gnomad AFR AF: 0.000566

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00243

Gnomad FIN AF: 0.0172

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00476

GnomAD3 exomes AF: 0.00699 AC: 1240 AN: 177456 Hom.: 6 AF XY: 0.00691 AC XY: 430 AN XY: 62268

Gnomad AFR exome AF: 0.000545

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00832

Gnomad EAS exome AF: 0.0000757

Gnomad SAS exome AF: 0.00361

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.00759

GnomAD4 exome AF: 0.00862 AC: 9356 AN: 1085214 Hom.: 42 Cov.: 28 AF XY: 0.00851 AC XY: 2989 AN XY: 351336

Gnomad4 AFR exome AF: 0.000574

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00955

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00467

Gnomad4 FIN exome AF: 0.0175

Gnomad4 NFE exome AF: 0.00932

Gnomad4 OTH exome AF: 0.00864

GnomAD4 genome AF: 0.00729 AC: 800 AN: 109734 Hom.: 9 Cov.: 21 AF XY: 0.00731 AC XY: 234 AN XY: 32014

Gnomad4 AFR AF: 0.000565

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00244

Gnomad4 FIN AF: 0.0172

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00470

Alfa AF: 0.0117 Hom.: 89

Bravo AF: 0.00614

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	Jun 06, 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	-0.75
CADD	Benign	1.2
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.040
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: rs185777707; hg19: chrX-107415766;