dbSNP rs1302611212: COL4A6:p.Arg1628Leu (chrX-108157190-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_033641.4(COL4A6):c.4883G>T(p.Arg1628Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,193 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1628Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

COL4A6
NM_033641.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.05

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), 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

COL4A6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A6	NM_033641.4	MANE Select	c.4883G>T	p.Arg1628Leu	missense	Exon 45 of 45	NP_378667.1	Q14031-2
COL4A6	NM_001287758.2		c.4934G>T	p.Arg1645Leu	missense	Exon 46 of 46	NP_001274687.1	A8MXH5
COL4A6	NM_001847.4		c.4886G>T	p.Arg1629Leu	missense	Exon 45 of 45	NP_001838.2	Q14031-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL4A6	ENST00000334504.12	TSL:5 MANE Select	c.4883G>T	p.Arg1628Leu	missense	Exon 45 of 45	ENSP00000334733.7	Q14031-2
COL4A6	ENST00000372216.8	TSL:1	c.4886G>T	p.Arg1629Leu	missense	Exon 45 of 45	ENSP00000361290.4	Q14031-1
COL4A6	ENST00000621266.4	TSL:1	c.4811G>T	p.Arg1604Leu	missense	Exon 44 of 44	ENSP00000482970.1	A0A087WZY5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098193

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363551

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842102

Other (OTH)

AF:

0.00

AC:

AN:

46096

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.64

BayesDel_noAF

Pathogenic

0.69

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

5.0

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.8

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.81

MutPred

0.71

Loss of methylation at R1629 (P = 0.0238)

MVP

0.99

MPC

0.24

ClinPred

0.98

GERP RS

5.0

Varity_R

0.78

gMVP

0.89

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over