rs143207434

chr1-211479040-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164688.2(RD3):c.584A>T(p.Asp195Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,596,836 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 33)
  • Exomes 𝑓: 0.010 (101 hom.)
• Consequence: RD3 NM_001164688.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.17

Genes affected

RD3 (HGNC:19689): (RD3 regulator of GUCY2D) This gene encodes a retinal protein that is associated with promyelocytic leukemia-gene product (PML) bodies in the nucleus. Mutations in this gene cause Leber congenital amaurosis type 12, a disease that results in retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005150646).
• BP6: Variant 1-211479040-T-A is Benign according to our data. Variant chr1-211479040-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 445480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-211479040-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1589/152316) while in subpopulation NFE AF= 0.0139 (942/68014). AF 95% confidence interval is 0.0131. There are 15 homozygotes in gnomad4. There are 835 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RD3	NM_001164688.2	c.584A>T	p.Asp195Val	missense_variant	3/3	ENST00000680073.1
RD3	NM_183059.3	c.584A>T	p.Asp195Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RD3	ENST00000680073.1	c.584A>T	p.Asp195Val	missense_variant	3/3		NM_001164688.2	P1
RD3	ENST00000367002.5	c.584A>T	p.Asp195Val	missense_variant	3/3	1		P1
RD3	ENST00000484910.1	n.552A>T		non_coding_transcript_exon_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1590 AN: 152198 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.00811

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00889 AC: 2097 AN: 235966 Hom.: 19 AF XY: 0.00875 AC XY: 1130 AN XY: 129104

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00495

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000465

Gnomad FIN exome AF: 0.0277

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00826

GnomAD4 exome AF: 0.0101 AC: 14584 AN: 1444520 Hom.: 101 Cov.: 33 AF XY: 0.0100 AC XY: 7175 AN XY: 717160

Gnomad4 AFR exome AF: 0.00150

Gnomad4 AMR exome AF: 0.00515

Gnomad4 ASJ exome AF: 0.00347

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000816

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00776

GnomAD4 genome AF: 0.0104 AC: 1589 AN: 152316 Hom.: 15 Cov.: 33 AF XY: 0.0112 AC XY: 835 AN XY: 74474

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00810

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0321

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.0114 Hom.: 10

Bravo AF: 0.00774

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.0124 AC: 107

ExAC AF: 0.00889 AC: 1076

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2017	- -

Leber congenital amaurosis 12 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.098
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.062	B
Vest4		0.26
MVP		0.47
MPC		1.1
ClinPred		0.015	T
GERP RS		4.3
Varity_R		0.20
gMVP		0.64

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: rs143207434; hg19: chr1-211652382; COSMIC: COSV65362588;