5-149858785-T-C

Position:

• chr5-149858785-T-C

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.*2110A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 145,368 control chromosomes in the GnomAD database, including 25,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (24997 hom., cov: 24)
  • Exomes 𝑓: 0.45 (15 hom.)
• Consequence: PDE6A NM_000440.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.03

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=-1.02).
• BP6: Variant 5-149858785-T-C is Benign according to our data. Variant chr5-149858785-T-C is described in ClinVar as [Benign]. Clinvar id is 351948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDE6A	NM_000440.3	c.*2110A>G		3_prime_UTR_variant	22/22	ENST00000255266.10	NP_000431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDE6A	ENST00000255266.10	c.*2110A>G		3_prime_UTR_variant	22/22	1	NM_000440.3	ENSP00000255266	P1
PDE6A	ENST00000508173.5	n.4877A>G		non_coding_transcript_exon_variant	20/20	1
PDE6A	ENST00000613228.1	c.*2110A>G		3_prime_UTR_variant	20/20	5		ENSP00000478060

Frequencies

GnomAD3 genomes AF: 0.583 AC: 84663 AN: 145172 Hom.: 24973 Cov.: 24

Gnomad AFR AF: 0.646

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.581

GnomAD4 exome AF: 0.446 AC: 41 AN: 92 Hom.: 15 Cov.: 0 AF XY: 0.486 AC XY: 34 AN XY: 70

Gnomad4 AFR exome AF: 0.667

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.444

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.583 AC: 84741 AN: 145276 Hom.: 24997 Cov.: 24 AF XY: 0.583 AC XY: 40887 AN XY: 70086

Gnomad4 AFR AF: 0.646

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.507

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.544

Gnomad4 NFE AF: 0.570

Gnomad4 OTH AF: 0.583

Alfa AF: 0.567 Hom.: 16899

Bravo AF: 0.589

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 12, 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	-1.0
CADD	Benign	0.48
DANN	Benign	0.11

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: rs759816; hg19: chr5-149238348;