NM_020366.4:c.3097G>C

Variant names:

• chr14-21328625-G-C
• rs3748361
• NM_020366.4:c.3097G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.3097G>C​(p.Glu1033Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,602,658 control chromosomes in the GnomAD database, including 97,013 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6860 hom., cov: 31)
  • Exomes 𝑓: 0.34 (90153 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005508
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.30
• Publications: 36 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 Submitted by: G2P
• Leber congenital amaurosis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00586462).
• BP6: Variant 14-21328625-G-C is Benign according to our data. Variant chr14-21328625-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

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.3097G>C	p.Glu1033Gln	missense splice_region	Exon 19 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2023G>C	p.Glu675Gln	missense splice_region	Exon 9 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1183G>C	p.Glu395Gln	missense splice_region	Exon 7 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.3097G>C	p.Glu1033Gln	missense splice_region	Exon 19 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.1522G>C	p.Glu508Gln	missense splice_region	Exon 7 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.1075G>C	p.Glu359Gln	missense splice_region	Exon 6 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes AF: 0.266 AC: 40432 AN: 151866 Hom.: 6860 Cov.: 31

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.377

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.285

GnomAD2 exomes AF: 0.331 AC: 82392 AN: 248546 AF XY: 0.345

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.198

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.413

Gnomad FIN exome AF: 0.390

Gnomad NFE exome AF: 0.351

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.345 AC: 500377 AN: 1450672 Hom.: 90153 Cov.: 28 AF XY: 0.350 AC XY: 252797 AN XY: 722254

African (AFR) AF: 0.0516 AC: 1722 AN: 33352

American (AMR) AF: 0.203 AC: 9090 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 6599 AN: 26068

East Asian (EAS) AF: 0.377 AC: 14952 AN: 39632

South Asian (SAS) AF: 0.477 AC: 40998 AN: 85966

European-Finnish (FIN) AF: 0.400 AC: 21326 AN: 53308

Middle Eastern (MID) AF: 0.275 AC: 1554 AN: 5648

European-Non Finnish (NFE) AF: 0.348 AC: 383930 AN: 1102012

Other (OTH) AF: 0.337 AC: 20206 AN: 60004

GnomAD4 genome AF: 0.266 AC: 40431 AN: 151986 Hom.: 6860 Cov.: 31 AF XY: 0.272 AC XY: 20183 AN XY: 74278

African (AFR) AF: 0.0631 AC: 2618 AN: 41512

American (AMR) AF: 0.231 AC: 3519 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 887 AN: 3466

East Asian (EAS) AF: 0.399 AC: 2059 AN: 5156

South Asian (SAS) AF: 0.487 AC: 2345 AN: 4812

European-Finnish (FIN) AF: 0.377 AC: 3970 AN: 10534

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24156 AN: 67950

Other (OTH) AF: 0.288 AC: 606 AN: 2104

Alfa AF: 0.337 Hom.: 7031

Bravo AF: 0.240

TwinsUK AF: 0.334 AC: 1239

ALSPAC AF: 0.361 AC: 1393

ESP6500AA AF: 0.0709 AC: 265

ESP6500EA AF: 0.352 AC: 2888

ExAC AF: 0.336 AC: 40626

Asia WGS AF: 0.453 AC: 1573 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.327

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.048
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.94	N
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.83	N
REVEL	Benign	0.11
Sift	Benign	0.99	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.039
MPC		0.065
ClinPred		0.00094	T
GERP RS		1.8
PromoterAI		0.040	Neutral
Varity_R		0.049
gMVP		0.27
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.018
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

Other links and lift over

dbSNP: rs3748361; hg19: chr14-21796784; COSMIC: COSV52846310; COSMIC: COSV52846310;