NM_033641.4:c.3139-4G>A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00002626
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.857
• Publications: 1 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: Benign. The variant received -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 VariationId is 258272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 XL gene

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>A		splice_region intron	N/A	NP_378667.1
	COL4A6	NM_001287758.2		c.3190-4G>A		splice_region intron	N/A	NP_001274687.1
	COL4A6	NM_001847.4		c.3142-4G>A		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>A		splice_region intron	N/A	ENSP00000334733.7
	COL4A6	ENST00000372216.8	TSL:1	c.3142-4G>A		splice_region intron	N/A	ENSP00000361290.4
	COL4A6	ENST00000621266.4	TSL:1	c.3139-4G>A		splice_region intron	N/A	ENSP00000482970.1

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 800 AN: 109689 Hom.: 9 Cov.: 21

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

GnomAD2 exomes AF: 0.00699 AC: 1240 AN: 177456 AF XY: 0.00691

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 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

African (AFR) AF: 0.000574 AC: 15 AN: 26129

American (AMR) AF: 0.00135 AC: 47 AN: 34853

Ashkenazi Jewish (ASJ) AF: 0.00955 AC: 183 AN: 19168

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

South Asian (SAS) AF: 0.00467 AC: 245 AN: 52499

European-Finnish (FIN) AF: 0.0175 AC: 705 AN: 40182

Middle Eastern (MID) AF: 0.000733 AC: 3 AN: 4095

European-Non Finnish (NFE) AF: 0.00932 AC: 7764 AN: 832737

Other (OTH) AF: 0.00864 AC: 394 AN: 45600

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

African (AFR) AF: 0.000565 AC: 17 AN: 30100

American (AMR) AF: 0.00340 AC: 35 AN: 10302

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 28 AN: 2623

East Asian (EAS) AF: 0.00 AC: 0 AN: 3487

South Asian (SAS) AF: 0.00244 AC: 6 AN: 2457

European-Finnish (FIN) AF: 0.0172 AC: 98 AN: 5699

Middle Eastern (MID) AF: 0.00467 AC: 1 AN: 214

European-Non Finnish (NFE) AF: 0.0100 AC: 529 AN: 52688

Other (OTH) AF: 0.00470 AC: 7 AN: 1490

Alfa AF: 0.0117 Hom.: 89

Bravo AF: 0.00614

ClinVar

ClinVar submissions as Germline

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	-0.75
CADD	Benign	1.2
DANN	Benign	0.47
PhyloP100		-0.86
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs185777707; hg19: chrX-107415766;