5-149944307-C-T

Variant names:

• chr5-149944307-C-T
• rs147010346
• NM_000440.3:c.367G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_000440.3(PDE6A):​c.367G>A​(p.Asp123Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D123Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PDE6A NM_000440.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.10
• Publications: 7 publications found

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]

PDE6A Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 43

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40099704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6A	NM_000440.3	c.367G>A	p.Asp123Asn	missense_variant	Exon 1 of 22	ENST00000255266.10	NP_000431.2
PDE6A	NM_001410788.1	c.367G>A	p.Asp123Asn	missense_variant	Exon 1 of 20		NP_001397717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6A	ENST00000255266.10	c.367G>A	p.Asp123Asn	missense_variant	Exon 1 of 22	1	NM_000440.3	ENSP00000255266.5
PDE6A	ENST00000508173.5	n.487G>A		non_coding_transcript_exon_variant	Exon 1 of 20	1
PDE6A	ENST00000613228.1	c.367G>A	p.Asp123Asn	missense_variant	Exon 1 of 20	5		ENSP00000478060.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;D;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.9	.;L;.
PhyloP100		6.1
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	.;D;.
REVEL	Benign	0.27
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.66	.;P;.
Vest4		0.18
MutPred		0.45		Gain of catalytic residue at D123 (P = 0.057);Gain of catalytic residue at D123 (P = 0.057);Gain of catalytic residue at D123 (P = 0.057);
MVP		0.85
MPC		0.18
ClinPred		0.97	D
GERP RS		5.6
PromoterAI		0.0060	Neutral
Varity_R		0.30
gMVP		0.23
Mutation Taster		=64/36	polymorphism

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: rs147010346; hg19: chr5-149323870;