rs17103671

Variant names:

• chr14-21343037-A-G
• rs17103671
• NM_020366.4:c.3341A>G

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.3341A>G​(p.Asp1114Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00646 in 1,611,002 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 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 0.025 (124 hom., cov: 31)
  • Exomes 𝑓: 0.0046 (141 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001004
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -1.98
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010194093).
• BP6: Variant 14-21343037-A-G is Benign according to our data. Variant chr14-21343037-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 4988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 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.3341A>G	p.Asp1114Gly	missense splice_region	Exon 22 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2267A>G	p.Asp756Gly	missense splice_region	Exon 12 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1427A>G	p.Asp476Gly	missense splice_region	Exon 10 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.3341A>G	p.Asp1114Gly	missense splice_region	Exon 22 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.1766A>G	p.Asp589Gly	missense splice_region	Exon 10 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.1319A>G	p.Asp440Gly	missense splice_region	Exon 9 of 12	ENSP00000372391.4	Q96KN7-4

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3763 AN: 152178 Hom.: 124 Cov.: 31

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.00836 AC: 2070 AN: 247588 AF XY: 0.00709

Gnomad AFR exome AF: 0.0819

Gnomad AMR exome AF: 0.00800

Gnomad ASJ exome AF: 0.0127

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.00455 AC: 6640 AN: 1458706 Hom.: 141 Cov.: 29 AF XY: 0.00424 AC XY: 3075 AN XY: 725684

African (AFR) AF: 0.0857 AC: 2854 AN: 33288

American (AMR) AF: 0.00910 AC: 403 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 274 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000536 AC: 46 AN: 85832

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53382

Middle Eastern (MID) AF: 0.0205 AC: 118 AN: 5752

European-Non Finnish (NFE) AF: 0.00210 AC: 2336 AN: 1110152

Other (OTH) AF: 0.0101 AC: 606 AN: 60260

GnomAD4 genome AF: 0.0248 AC: 3774 AN: 152296 Hom.: 124 Cov.: 31 AF XY: 0.0240 AC XY: 1790 AN XY: 74480

African (AFR) AF: 0.0785 AC: 3259 AN: 41536

American (AMR) AF: 0.0155 AC: 237 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68034

Other (OTH) AF: 0.0199 AC: 42 AN: 2114

Alfa AF: 0.0102 Hom.: 161

Bravo AF: 0.0277

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0742 AC: 282

ESP6500EA AF: 0.00425 AC: 35

ExAC AF: 0.00911 AC: 1101

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
1	-	1	Leber congenital amaurosis 6 (2)
-	-	2	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (2)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.068
DANN	Benign	0.84
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-2.0
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.17
Sift	Benign	0.27	T
Sift4G	Benign	0.22	T
Polyphen		0.0070	B
Vest4		0.11
MVP		0.65
MPC		0.086
ClinPred		0.0063	T
GERP RS		-1.8
Varity_R		0.16
gMVP		0.24
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.020		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: rs17103671; hg19: chr14-21811196; COSMIC: COSV52847485;