X-108179444-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_033641.4(COL4A6):c.2132-6G>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 0.000909 in 1,177,527 control chromosomes in the GnomAD database, including 2 homozygotes. There are 336 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., 36 hem., cov: 22)

Exomes 𝑓: 0.00089 ( 1 hom. 300 hem. )

Consequence

COL4A6
NM_033641.4 splice_region, intron

Scores

Splicing: ADA: 0.00002499

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0380

Publications

0 publications found

Variant links:

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

COL4A6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant X-108179444-C-T is Benign according to our data. Variant chrX-108179444-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A6	NM_033641.4 link	c.2132-6G>A		splice_region_variant, intron_variant	Intron 25 of 44	ENST00000334504.12	NP_378667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A6	ENST00000334504.12 link	c.2132-6G>A		splice_region_variant, intron_variant	Intron 25 of 44	5	NM_033641.4	ENSP00000334733.7

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

118

AN:

112120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.0599

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00474

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00109

AC:

181

AN:

166367

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.000158

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00479

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000894

AC:

952

AN:

1065354

Hom.:

Cov.:

AF XY:

0.000894

AC XY:

300

AN XY:

335582

show subpopulations

African (AFR)

AF:

0.000118

AC:

AN:

25463

American (AMR)

AF:

0.00

AC:

AN:

33172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18344

East Asian (EAS)

AF:

0.00

AC:

AN:

29867

South Asian (SAS)

AF:

0.0000198

AC:

AN:

50606

European-Finnish (FIN)

AF:

0.00529

AC:

212

AN:

40059

Middle Eastern (MID)

AF:

0.000320

AC:

AN:

3121

European-Non Finnish (NFE)

AF:

0.000846

AC:

694

AN:

819957

Other (OTH)

AF:

0.000916

AC:

AN:

44765

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00105

AC:

118

AN:

112173

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

34363

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30920

American (AMR)

AF:

0.00

AC:

AN:

10652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.00474

AC:

AN:

6114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000883

AC:

AN:

53207

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000703

Hom.:

Bravo

AF:

0.000759

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, X-linked 6

Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.4

(source)

DANN

Benign

0.57

PhyloP100

0.038

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000025

dbscSNV1_RF

Benign

0.0040

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over