rs779748859

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PP3PP5_ModerateBS2

The NM_001287758.2(COL4A6):c.1768G>A(p.Gly590Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000215 in 1,117,009 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000021 ( 0 hom. 7 hem. )

Consequence

COL4A6
NM_001287758.2 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.38

Publications

4 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: Likely_benign. The variant received -1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant X-108187279-C-T is Pathogenic according to our data. Variant chrX-108187279-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 102425.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 7 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001287758.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL4A6	NM_033641.4	MANE Select	c.1768G>A	p.Gly590Ser	missense splice_region	Exon 23 of 45	NP_378667.1
COL4A6	NM_001287758.2		c.1768G>A	p.Gly590Ser	missense splice_region	Exon 23 of 46	NP_001274687.1
COL4A6	NM_001847.4		c.1771G>A	p.Gly591Ser	missense splice_region	Exon 23 of 45	NP_001838.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.1768G>A	p.Gly590Ser	missense splice_region	Exon 23 of 45	ENSP00000334733.7
COL4A6	ENST00000372216.8	TSL:1	c.1771G>A	p.Gly591Ser	missense splice_region	Exon 23 of 45	ENSP00000361290.4
COL4A6	ENST00000621266.4	TSL:1	c.1768G>A	p.Gly590Ser	missense splice_region	Exon 23 of 44	ENSP00000482970.1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000565

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000142

AC:

AN:

140975

AF XY:

0.0000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000301

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1005235

Hom.:

Cov.:

AF XY:

0.0000230

AC XY:

AN XY:

304121

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23703

American (AMR)

AF:

0.00

AC:

AN:

26551

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16022

East Asian (EAS)

AF:

0.00

AC:

AN:

28033

South Asian (SAS)

AF:

0.00

AC:

AN:

37972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37623

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3731

European-Non Finnish (NFE)

AF:

0.0000266

AC:

AN:

790011

Other (OTH)

AF:

0.00

AC:

AN:

41589

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111774

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33998

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30685

American (AMR)

AF:

0.00

AC:

AN:

10544

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2629

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6140

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000565

AC:

AN:

53143

Other (OTH)

AF:

0.00

AC:

AN:

1503

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00380082), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000718

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.00000826

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hearing loss, X-linked 6 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.74

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

PhyloP100

6.4

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.82

MutPred

0.91

Gain of relative solvent accessibility (P = 0.0023)

MVP

1.0

MPC

0.73

ClinPred

0.95

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.94

Mutation Taster

=60/40

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over