rs73251797

Variant names:

• chrX-108159454-G-A
• rs73251797
• NM_033641.4:c.4812+8C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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]

COL4A6 Gene-Disease associations (from GenCC):

• hearing loss, X-linked 6

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• X-linked nonsyndromic hearing loss

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• premature ovarian failure 1

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033641.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	NM_033641.4	MANE Select	c.4812+8C>T		splice_region intron	N/A	NP_378667.1	Q14031-2
	COL4A6	NM_001287758.2		c.4863+8C>T		splice_region intron	N/A	NP_001274687.1	A8MXH5
	COL4A6	NM_001847.4		c.4815+8C>T		splice_region intron	N/A	NP_001838.2	Q14031-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.4812+8C>T		splice_region intron	N/A	ENSP00000334733.7	Q14031-2
	COL4A6	ENST00000372216.8	TSL:1	c.4815+8C>T		splice_region intron	N/A	ENSP00000361290.4	Q14031-1
	COL4A6	ENST00000621266.4	TSL:1	c.4740+8C>T		splice_region intron	N/A	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 5729 AN: 112291 Hom.: 126 Cov.: 23

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

GnomAD2 exomes AF: 0.0502 AC: 9074 AN: 180829 AF XY: 0.0477

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 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

African (AFR) AF: 0.0560 AC: 1478 AN: 26389

American (AMR) AF: 0.0455 AC: 1598 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 788 AN: 19361

East Asian (EAS) AF: 0.0715 AC: 2160 AN: 30198

South Asian (SAS) AF: 0.0393 AC: 2123 AN: 54068

European-Finnish (FIN) AF: 0.0376 AC: 1523 AN: 40463

Middle Eastern (MID) AF: 0.0779 AC: 321 AN: 4121

European-Non Finnish (NFE) AF: 0.0455 AC: 38327 AN: 841798

Other (OTH) AF: 0.0494 AC: 2275 AN: 46064

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

African (AFR) AF: 0.0561 AC: 1735 AN: 30902

American (AMR) AF: 0.0425 AC: 454 AN: 10684

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 102 AN: 2650

East Asian (EAS) AF: 0.0944 AC: 333 AN: 3529

South Asian (SAS) AF: 0.0386 AC: 104 AN: 2697

European-Finnish (FIN) AF: 0.0342 AC: 212 AN: 6203

Middle Eastern (MID) AF: 0.0602 AC: 13 AN: 216

European-Non Finnish (NFE) AF: 0.0485 AC: 2585 AN: 53246

Other (OTH) AF: 0.0378 AC: 58 AN: 1536

Alfa AF: 0.0501 Hom.: 508

Bravo AF: 0.0530

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Hearing loss, X-linked 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.2
DANN	Benign	0.79
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs73251797; hg19: chrX-107402684;