chrX-108178968-C-T

Variant names:

• chrX-108178968-C-T
• rs150847883
• NM_033641.4:c.2354-123G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033641.4(COL4A6):​c.2354-123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 847,367 control chromosomes in the GnomAD database, including 99 homozygotes. There are 3,363 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (16 hom., 495 hem., cov: 23)
  • Exomes 𝑓: 0.015 (83 hom. 2868 hem.)
• Consequence: COL4A6 NM_033641.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.172

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-108178968-C-T is Benign according to our data. Variant chrX-108178968-C-T is described in ClinVar as [Benign]. Clinvar id is 1260343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0135 (1515/112506) while in subpopulation NFE AF = 0.0165 (881/53265). AF 95% confidence interval is 0.0156. There are 16 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4	c.2354-123G>A		intron_variant	Intron 26 of 44	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12	c.2354-123G>A		intron_variant	Intron 26 of 44	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1516 AN: 112452 Hom.: 16 Cov.: 23

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0598

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0165

GnomAD4 exome AF: 0.0145 AC: 10692 AN: 734861 Hom.: 83 AF XY: 0.0162 AC XY: 2868 AN XY: 176579

African (AFR) AF: 0.00134 AC: 24 AN: 17937

American (AMR) AF: 0.00998 AC: 167 AN: 16730

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 416 AN: 12643

East Asian (EAS) AF: 0.00 AC: 0 AN: 26050

South Asian (SAS) AF: 0.00199 AC: 67 AN: 33601

European-Finnish (FIN) AF: 0.0454 AC: 1174 AN: 25840

Middle Eastern (MID) AF: 0.0136 AC: 37 AN: 2726

European-Non Finnish (NFE) AF: 0.0147 AC: 8324 AN: 565953

Other (OTH) AF: 0.0145 AC: 483 AN: 33381

GnomAD4 genome AF: 0.0135 AC: 1515 AN: 112506 Hom.: 16 Cov.: 23 AF XY: 0.0143 AC XY: 495 AN XY: 34688

African (AFR) AF: 0.00180 AC: 56 AN: 31036

American (AMR) AF: 0.0130 AC: 139 AN: 10706

Ashkenazi Jewish (ASJ) AF: 0.0306 AC: 81 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3575

South Asian (SAS) AF: 0.00186 AC: 5 AN: 2695

European-Finnish (FIN) AF: 0.0458 AC: 281 AN: 6138

Middle Eastern (MID) AF: 0.0276 AC: 6 AN: 217

European-Non Finnish (NFE) AF: 0.0165 AC: 881 AN: 53265

Other (OTH) AF: 0.0163 AC: 25 AN: 1537

Alfa AF: 0.0191 Hom.: 98

Bravo AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.69
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs150847883; hg19: chrX-107422198;