rs185777707

Variant names:

• chrX-108172536-C-A
• rs185777707
• NM_033641.4:c.3139-4G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-108172536-C-A
• chrX-108172536-C-G
• chrX-108172536-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033641.4(COL4A6):​c.3139-4G>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 0.000000921 in 1,085,273 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: COL4A6 NM_033641.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002779
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.857
• Publications: 0 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), ClinGen, Ambry Genetics, PanelApp Australia
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	NM_033641.4	MANE Select	c.3139-4G>T		splice_region intron	N/A	NP_378667.1
	COL4A6	NM_001287758.2		c.3190-4G>T		splice_region intron	N/A	NP_001274687.1
	COL4A6	NM_001847.4		c.3142-4G>T		splice_region intron	N/A	NP_001838.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.3139-4G>T		splice_region intron	N/A	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.3142-4G>T		splice_region intron	N/A	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.3139-4G>T		splice_region intron	N/A	ENSP00000482970.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1085273 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 351339

African (AFR) AF: 0.00 AC: 0 AN: 26129

American (AMR) AF: 0.00 AC: 0 AN: 34853

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19170

East Asian (EAS) AF: 0.00 AC: 0 AN: 29951

South Asian (SAS) AF: 0.00 AC: 0 AN: 52499

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4095

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832792

Other (OTH) AF: 0.00 AC: 0 AN: 45602

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.1
DANN	Benign	0.52
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.040
SpliceAI score (max)		0.080		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: rs185777707; hg19: chrX-107415766;