5-149858353-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000440.3(PDE6A):c.*2542G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 152,068 control chromosomes in the GnomAD database, including 11,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11159 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE6A NM_000440.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

Genes affected

PDE6A (HGNC:8785): (phosphodiesterase 6A) This gene encodes the cyclic-GMP (cGMP)-specific phosphodiesterase 6A alpha subunit, expressed in cells of the retinal rod outer segment. The phosphodiesterase 6 holoenzyme is a heterotrimer composed of an alpha, beta, and two gamma subunits. cGMP is an important regulator of rod cell membrane current, and its dynamic concentration is established by phosphodiesterase 6A cGMP hydrolysis and guanylate cyclase cGMP synthesis. The protein is a subunit of a key phototransduction enzyme and participates in processes of transmission and amplification of the visual signal. Mutations in this gene have been identified as one cause of autosomal recessive retinitis pigmentosa. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-149858353-C-T is Benign according to our data. Variant chr5-149858353-C-T is described in ClinVar as [Benign]. Clinvar id is 351943.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6A	NM_000440.3	c.*2542G>A		3_prime_UTR_variant	22/22	ENST00000255266.10
PDE6A	NM_001410788.1	c.*2542G>A		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6A	ENST00000255266.10	c.*2542G>A		3_prime_UTR_variant	22/22	1	NM_000440.3	P1
PDE6A	ENST00000508173.5	n.5309G>A		non_coding_transcript_exon_variant	20/20	1
PDE6A	ENST00000613228.1	c.*2542G>A		3_prime_UTR_variant	20/20	5

Frequencies

GnomAD3 genomes AF: 0.374 AC: 56775 AN: 151950 Hom.: 11143 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.374

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.374 AC: 56838 AN: 152068 Hom.: 11159 Cov.: 32 AF XY: 0.374 AC XY: 27789 AN XY: 74324

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.433

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.428

Gnomad4 OTH AF: 0.377

Alfa AF: 0.410 Hom.: 18098

Bravo AF: 0.368

Asia WGS AF: 0.326 AC: 1131 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.6
Dann	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs30884; hg19: chr5-149237916;