5-149858495-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000440.3(PDE6A):c.*2400G>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 0.0197 in 152,302 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.020 (41 hom., cov: 33)
  • Exomes 𝑓: 0.015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PDE6A NM_000440.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.177

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0197 (3003/152302) while in subpopulation NFE AF= 0.0295 (2004/68042). AF 95% confidence interval is 0.0284. There are 41 homozygotes in gnomad4. There are 1448 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDE6A	NM_000440.3	c.*2400G>A		3_prime_UTR_variant	22/22	ENST00000255266.10
PDE6A	NM_001410788.1	c.*2400G>A		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDE6A	ENST00000255266.10	c.*2400G>A		3_prime_UTR_variant	22/22	1	NM_000440.3	P1
PDE6A	ENST00000508173.5	n.5167G>A		non_coding_transcript_exon_variant	20/20	1
PDE6A	ENST00000613228.1	c.*2400G>A		3_prime_UTR_variant	20/20	5

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 3001 AN: 152184 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00975

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0158

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0147 AC: 1 AN: 68 Hom.: 0 Cov.: 0 AF XY: 0.0192 AC XY: 1 AN XY: 52

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0197 AC: 3003 AN: 152302 Hom.: 41 Cov.: 33 AF XY: 0.0194 AC XY: 1448 AN XY: 74480

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.0389

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0160

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0295

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0184 Hom.: 12

Bravo AF: 0.0169

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.9
Dann	Benign	0.76

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: rs74771814; hg19: chr5-149238058;