chr5-149858495-C-T

Variant names:

• chr5-149858495-C-T
• rs74771814
• NM_000440.3:c.*2400G>A

Variant summary

Our verdict is Benign. The variant received -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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.177
• Publications: 3 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):

• PDE6A-related retinopathy

  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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 41 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000440.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	NM_000440.3	MANE Select	c.*2400G>A		3_prime_UTR	Exon 22 of 22	NP_000431.2	P16499
	PDE6A	NM_001410788.1		c.*2400G>A		3_prime_UTR	Exon 20 of 20	NP_001397717.1	F1T0K3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDE6A	ENST00000255266.10	TSL:1 MANE Select	c.*2400G>A		3_prime_UTR	Exon 22 of 22	ENSP00000255266.5	P16499
	PDE6A	ENST00000508173.5	TSL:1	n.5167G>A		non_coding_transcript_exon	Exon 20 of 20
	PDE6A	ENST00000613228.1	TSL:5	c.*2400G>A		3_prime_UTR	Exon 20 of 20	ENSP00000478060.1	F1T0K3

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0185 AC: 1 AN: 54

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.00517 AC: 215 AN: 41564

American (AMR) AF: 0.00974 AC: 149 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4824

European-Finnish (FIN) AF: 0.0351 AC: 372 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2004 AN: 68042

Other (OTH) AF: 0.0156 AC: 33 AN: 2110

Alfa AF: 0.0253 Hom.: 79

Bravo AF: 0.0169

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		-0.18
Mutation Taster		=100/0	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: rs74771814; hg19: chr5-149238058;