1-211479040-T-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/21 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.17

Publications

8 publications found

Variant links:

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]

RD3 Gene-Disease associations (from GenCC):

Leber congenital amaurosis 12
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 445480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RD3	NM_001164688.2 link	c.584A>T	p.Asp195Val	missense_variant	Exon 3 of 3	ENST00000680073.1	NP_001158160.1	Q7Z3Z2
RD3	NM_183059.3 link	c.584A>T	p.Asp195Val	missense_variant	Exon 3 of 3		NP_898882.1	Q7Z3Z2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RD3	ENST00000680073.1 link	c.584A>T	p.Asp195Val	missense_variant	Exon 3 of 3		NM_001164688.2	ENSP00000505312.1	Q7Z3Z2
RD3	ENST00000367002.5 link	c.584A>T	p.Asp195Val	missense_variant	Exon 3 of 3	1		ENSP00000355969.4	Q7Z3Z2
RD3	ENST00000484910.1 link	n.552A>T		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1590

AN:

152198

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00889

AC:

2097

AN:

235966

AF XY:

0.00875

show subpopulations

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 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.:

AF XY:

0.0100

AC XY:

7175

AN XY:

717160

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

33268

American (AMR)

AF:

0.00515

AC:

229

AN:

44426

Ashkenazi Jewish (ASJ)

AF:

0.00347

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39432

South Asian (SAS)

AF:

0.000816

AC:

AN:

85766

European-Finnish (FIN)

AF:

0.0287

AC:

1290

AN:

44906

Middle Eastern (MID)

AF:

0.00160

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0112

AC:

12383

AN:

1105464

Other (OTH)

AF:

0.00776

AC:

463

AN:

59656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

765

1530

2296

3061

3826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

400

800

1200

1600

2000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0104

AC:

1589

AN:

152316

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

835

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00188

AC:

AN:

41580

American (AMR)

AF:

0.00810

AC:

124

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0321

AC:

341

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0139

AC:

942

AN:

68014

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00774

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.0124

AC:

107

ExAC

AF:

0.00889

AC:

1076

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0118

EpiControl

AF:

0.0111

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 14, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Leber congenital amaurosis 12

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 19, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

3.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.2

REVEL

Benign

0.098

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

0.062

Vest4

0.26

MVP

0.47

MPC

1.1

ClinPred

0.015

GERP RS

4.3

Varity_R

0.20

gMVP

0.64

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over