chr1-211479040-T-A

Position:

chr1-211479040-T-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RD3	NM_001164688.2 linkuse as main transcript	c.584A>T	p.Asp195Val	missense_variant	3/3	ENST00000680073.1	NP_001158160.1
RD3	NM_183059.3 linkuse as main transcript	c.584A>T	p.Asp195Val	missense_variant	3/3		NP_898882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RD3	ENST00000680073.1 linkuse as main transcript	c.584A>T	p.Asp195Val	missense_variant	3/3		NM_001164688.2	ENSP00000505312	P1
RD3	ENST00000367002.5 linkuse as main transcript	c.584A>T	p.Asp195Val	missense_variant	3/3	1		ENSP00000355969	P1
RD3	ENST00000484910.1 linkuse as main transcript	n.552A>T		non_coding_transcript_exon_variant	2/2	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

GnomAD3 exomes

AF:

0.00889

AC:

2097

AN:

235966

Hom.:

AF XY:

0.00875

AC XY:

1130

AN XY:

129104

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 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.:

AF XY:

0.0100

AC XY:

7175

AN XY:

717160

show subpopulations

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.:

Cov.:

AF XY:

0.0112

AC XY:

835

AN XY:

74474

show subpopulations

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.:

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

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

Leber congenital amaurosis 12

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

BayesDel_noAF

Benign

-0.59

CADD

Benign

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

MutationTaster

Benign

1.0

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over