dbSNP rs145896974: RPGRIP1:p.Leu762Leu (chr14-21325300-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_020366.4(RPGRIP1):c.2284C>T(p.Leu762Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00285 in 1,612,554 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L762L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 18 hom. )

Consequence

RPGRIP1
NM_020366.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:10

Conservation

PhyloP100: 2.84

Publications

2 publications found

Variant links:

Genes affected

RPGRIP1 (HGNC:13436): (RPGR interacting protein 1) This gene encodes a photoreceptor protein that interacts with retinitis pigmentosa GTPase regulator protein and is a key component of cone and rod photoreceptor cells. Mutations in this gene lead to autosomal recessive congenital blindness. [provided by RefSeq, Oct 2008]

RPGRIP1 Gene-Disease associations (from GenCC):

cone-rod dystrophy 13
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P
Leber congenital amaurosis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Leber congenital amaurosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RPGRIP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 14-21325300-C-T is Benign according to our data. Variant chr14-21325300-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285038.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00248 (378/152304) while in subpopulation NFE AF = 0.00365 (248/68022). AF 95% confidence interval is 0.00327. There are 1 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 18 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020366.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGRIP1	NM_020366.4	MANE Select	c.2284C>T	p.Leu762Leu	synonymous	Exon 16 of 25	NP_065099.3
RPGRIP1	NM_001377948.1		c.1210C>T	p.Leu404Leu	synonymous	Exon 6 of 15	NP_001364877.1
RPGRIP1	NM_001377949.1		c.796+575C>T		intron	N/A	NP_001364878.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2284C>T	p.Leu762Leu	synonymous	Exon 16 of 25	ENSP00000382895.2	Q96KN7-1
RPGRIP1	ENST00000555587.5	TSL:1	c.709C>T	p.Leu237Leu	synonymous	Exon 4 of 13	ENSP00000451262.1	G3V3I7
RPGRIP1	ENST00000382933.8	TSL:1	c.689-2323C>T		intron	N/A	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

380

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00365

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00329

AC:

809

AN:

245544

AF XY:

0.00356

show subpopulations

Gnomad AFR exome

AF:

0.000329

Gnomad AMR exome

AF:

0.000971

Gnomad ASJ exome

AF:

0.0182

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00154

Gnomad NFE exome

AF:

0.00334

Gnomad OTH exome

AF:

0.00401

GnomAD4 exome

AF:

0.00289

AC:

4217

AN:

1460250

Hom.:

Cov.:

AF XY:

0.00307

AC XY:

2227

AN XY:

726294

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33460

American (AMR)

AF:

0.00115

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.0180

AC:

469

AN:

26070

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00536

AC:

461

AN:

86010

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00259

AC:

2873

AN:

1111214

Other (OTH)

AF:

0.00356

AC:

215

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

233

466

699

932

1165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

106

212

318

424

530

<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:

0.00248

AC:

378

AN:

152304

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41578

American (AMR)

AF:

0.00124

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00331

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00365

AC:

248

AN:

68022

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00347

Hom.:

Bravo

AF:

0.00242

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Cone-rod dystrophy 13 (2)

Leber congenital amaurosis 6 (2)

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)

not specified (1)

Retinal dystrophy (1)

RPGRIP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

7.7

(source)

DANN

Benign

0.73

PhyloP100

2.8

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over