11-31789936-A-T

Variant names:

• chr11-31789936-A-T
• rs750848278
• NM_001368894.2:c.1309T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM4 BP6_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
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 4.95
• Publications: 1 publications found

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]

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
• ocular dysgenesis caused by defects in PAX6 regulation

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• aniridia 1

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001368894.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	NM_001368894.2	MANE Select	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	NP_001355823.1	P26367-2
	ELP4	NM_019040.5	MANE Select	c.*6412A>T		3_prime_UTR	Exon 10 of 10	NP_061913.3
	PAX6	NM_001368910.2		c.1510T>A	p.Ter504Lysext*?	stop_lost	Exon 14 of 14	NP_001355839.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX6	ENST00000640368.2	TSL:5 MANE Select	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	ENSP00000492024.1	P26367-2
	PAX6	ENST00000419022.6	TSL:1	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	ENSP00000404100.1	P26367-2
	PAX6	ENST00000638914.3	TSL:1	c.1309T>A	p.Ter437Lysext*?	stop_lost	Exon 14 of 14	ENSP00000492315.2	P26367-2

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 1943 AN: 53640 Hom.: 0 Cov.: 0

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

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.: 0 Cov.: 26 AF XY: 0.00185 AC XY: 803 AN XY: 434382

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: 85 AN: 15970

East Asian (EAS) AF: 0.000550 AC: 15 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: 13 AN: 2634

European-Non Finnish (NFE) AF: 0.000636 AC: 428 AN: 672532

Other (OTH) AF: 0.00191 AC: 70 AN: 36602

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0362 AC: 1941 AN: 53628 Hom.: 0 Cov.: 0 AF XY: 0.0338 AC XY: 855 AN XY: 25310

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: 49 AN: 1388

East Asian (EAS) AF: 0.0446 AC: 96 AN: 2154

South Asian (SAS) AF: 0.0155 AC: 31 AN: 2000

European-Finnish (FIN) AF: 0.00944 AC: 27 AN: 2860

Middle Eastern (MID) AF: 0.0122 AC: 1 AN: 82

European-Non Finnish (NFE) AF: 0.0401 AC: 1167 AN: 29114

Other (OTH) AF: 0.0318 AC: 23 AN: 724

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.62
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.43	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.89	T
PhyloP100		5.0
ClinPred		0.021	T
GERP RS		6.2
Mutation Taster		=3/197	disease causing

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

Other links and lift over

dbSNP: rs750848278; hg19: chr11-31811484; COSMIC: COSV53793768; COSMIC: COSV53793768;