NM_001368894.2:c.1309T>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM4BP6_Moderate

The NM_001368894.2(PAX6):c.1309T>A(p.Ter437Lysext*?) variant causes a stop lost change. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.036 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0020 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAX6
NM_001368894.2 stop_lost

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:4

Conservation

PhyloP100: 4.95

Publications

1 publications found

Variant links:

Genes affected

PAX6 (HGNC:8620): (paired box 6) This gene encodes paired box protein Pax-6, one of many human homologs of the Drosophila melanogaster gene prd. In addition to a conserved paired box domain, a hallmark feature of this gene family, the encoded protein also contains a homeobox domain. Both domains are known to bind DNA and function as regulators of gene transcription. Activity of this protein is key in the development of neural tissues, particularly the eye. This gene is regulated by multiple enhancers located up to hundreds of kilobases distant from this locus. Mutations in this gene or in the enhancer regions can cause ocular disorders such as aniridia and Peter's anomaly. Use of alternate promoters and alternative splicing results in multiple transcript variants encoding different isoforms. Interestingly, inclusion of a particular alternate coding exon has been shown to increase the length of the paired box domain and alter its DNA binding specificity. Consequently, isoforms that carry the shorter paired box domain regulate a different set of genes compared to the isoforms carrying the longer paired box domain. [provided by RefSeq, Mar 2019]

PAX6 links:

ELP4 (HGNC:1171): (elongator acetyltransferase complex subunit 4) This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. This gene has also been associated with Rolandic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ELP4 Gene-Disease associations (from GenCC):

aniridia 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp
aniridia 1
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ELP4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM4

Stoplost variant in NM_001368894.2 Downstream stopcodon found after 33 codons.

BP6

Variant 11-31789936-A-T is Benign according to our data. Variant chr11-31789936-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 676688.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX6	NM_001368894.2 link	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	ENST00000640368.2	NP_001355823.1
ELP4	NM_019040.5 link	c.*6412A>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000640961.2	NP_061913.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX6	ENST00000640368.2 link	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	5	NM_001368894.2	ENSP00000492024.1
ELP4	ENST00000640961.2 link	c.*6412A>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_019040.5	ENSP00000492152.1

Frequencies

GnomAD3 genomes

AF:

0.0362

AC:

1943

AN:

53640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0409

Gnomad AMI

AF:

0.0719

Gnomad AMR

AF:

0.0231

Gnomad ASJ

AF:

0.0353

Gnomad EAS

AF:

0.0449

Gnomad SAS

AF:

0.0159

Gnomad FIN

AF:

0.00944

Gnomad MID

AF:

0.0213

Gnomad NFE

AF:

0.0401

Gnomad OTH

AF:

0.0319

GnomAD2 exomes

AF:

0.0182

AC:

2051

AN:

112980

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00719

Gnomad AMR exome

AF:

0.0473

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.0184

Gnomad FIN exome

AF:

0.00758

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0281

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00204

AC:

1768

AN:

867268

Hom.:

Cov.:

AF XY:

0.00185

AC XY:

803

AN XY:

434382

show subpopulations

African (AFR)

AF:

0.00606

AC:

105

AN:

17340

American (AMR)

AF:

0.0253

AC:

501

AN:

19770

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

AN:

15970

East Asian (EAS)

AF:

0.000550

AC:

AN:

27288

South Asian (SAS)

AF:

0.00531

AC:

207

AN:

38970

European-Finnish (FIN)

AF:

0.00951

AC:

344

AN:

36162

Middle Eastern (MID)

AF:

0.00494

AC:

AN:

2634

European-Non Finnish (NFE)

AF:

0.000636

AC:

428

AN:

672532

Other (OTH)

AF:

0.00191

AC:

AN:

36602

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

134

200

267

334

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0362

AC:

1941

AN:

53628

Hom.:

Cov.:

AF XY:

0.0338

AC XY:

855

AN XY:

25310

show subpopulations

African (AFR)

AF:

0.0408

AC:

409

AN:

10026

American (AMR)

AF:

0.0233

AC:

116

AN:

4974

Ashkenazi Jewish (ASJ)

AF:

0.0353

AC:

AN:

1388

East Asian (EAS)

AF:

0.0446

AC:

AN:

2154

South Asian (SAS)

AF:

0.0155

AC:

AN:

2000

European-Finnish (FIN)

AF:

0.00944

AC:

AN:

2860

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0401

AC:

1167

AN:

29114

Other (OTH)

AF:

0.0318

AC:

AN:

724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

179

268

358

447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

112

140

<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:

0.00

Hom.:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.62

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.43

T;T

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.89

PhyloP100

5.0

ClinPred

0.021

GERP RS

6.2

Mutation Taster

=3/197

disease causing

(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

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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