rs147586703

Variant names:

• chr14-21321995-C-T
• rs147586703
• NM_020366.4:c.1753C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020366.4(RPGRIP1):​c.1753C>T​(p.Pro585Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,612,198 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (3 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 0.746
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0085558).
• BP6: Variant 14-21321995-C-T is Benign according to our data. Variant chr14-21321995-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283795.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00149 (227/152300) while in subpopulation NFE AF = 0.00222 (151/68028). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.1753C>T	p.Pro585Ser	missense	Exon 14 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.679C>T	p.Pro227Ser	missense	Exon 4 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.679C>T	p.Pro227Ser	missense	Exon 4 of 13	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.1753C>T	p.Pro585Ser	missense	Exon 14 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.178C>T	p.Pro60Ser	missense	Exon 2 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.679C>T	p.Pro227Ser	missense	Exon 4 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00222

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00168 AC: 414 AN: 247034 AF XY: 0.00175

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.000354

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00331

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00269 AC: 3933 AN: 1459898 Hom.: 3 Cov.: 31 AF XY: 0.00261 AC XY: 1896 AN XY: 726214

African (AFR) AF: 0.000450 AC: 15 AN: 33334

American (AMR) AF: 0.000587 AC: 26 AN: 44300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85906

European-Finnish (FIN) AF: 0.00339 AC: 181 AN: 53372

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00324 AC: 3599 AN: 1111250

Other (OTH) AF: 0.00181 AC: 109 AN: 60260

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00145 AC XY: 108 AN XY: 74464

African (AFR) AF: 0.000674 AC: 28 AN: 41558

American (AMR) AF: 0.00124 AC: 19 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00222 AC: 151 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00183 Hom.: 0

Bravo AF: 0.00143

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.00156 AC: 189

EpiCase AF: 0.00218

EpiControl AF: 0.00207

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	2	Leber congenital amaurosis 6 (2)
-	1	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (2)
-	-	1	Cone-rod dystrophy 13 (1)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.63	T
PhyloP100		0.75
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.51	P
Vest4		0.48
MVP		0.79
MPC		0.15
ClinPred		0.025	T
GERP RS		3.7
Varity_R		0.13
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs147586703; hg19: chr14-21790154;