5-149907345-G-T

Variant names:

• chr5-149907345-G-T
• rs121918577
• NM_000440.3:c.1032C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000440.3(PDE6A):​c.1032C>A​(p.Ser344Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. S344S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PDE6A NM_000440.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.435
• Publications: 8 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 5-149907345-G-T is Pathogenic according to our data. Variant chr5-149907345-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13111.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDE6A	NM_000440.3	c.1032C>A	p.Ser344Arg	missense_variant	Exon 7 of 22	ENST00000255266.10	NP_000431.2
PDE6A	NM_001410788.1	c.789C>A	p.Ser263Arg	missense_variant	Exon 5 of 20		NP_001397717.1
PDE6A	XM_011537650.3	c.147C>A	p.Ser49Arg	missense_variant	Exon 4 of 19		XP_011535952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDE6A	ENST00000255266.10	c.1032C>A	p.Ser344Arg	missense_variant	Exon 7 of 22	1	NM_000440.3	ENSP00000255266.5
PDE6A	ENST00000508173.5	n.1152C>A		non_coding_transcript_exon_variant	Exon 7 of 20	1
PDE6A	ENST00000613228.1	c.789C>A	p.Ser263Arg	missense_variant	Exon 5 of 20	5		ENSP00000478060.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461608 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

African (AFR) AF: 0.00 AC: 0 AN: 33476

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 43 Pathogenic:1

Dec 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	5.3
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;D;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		-0.43
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	.;D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.016	.;D;.
Sift4G	Uncertain	0.043	D;T;D
Polyphen		0.99	.;D;.
Vest4		0.91
MutPred		0.81		.;Loss of glycosylation at S344 (P = 0.005);.;
MVP		0.78
MPC		0.53
ClinPred		0.99	D
GERP RS		-5.3
Varity_R		0.60
gMVP		0.52
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.050		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: rs121918577; hg19: chr5-149286908;