rs6571751

Variant names:

• chr14-21302571-A-G
• rs6571751
• NM_020366.4:c.574A>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.574A>G​(p.Lys192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,561,794 control chromosomes in the GnomAD database, including 196,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18322 hom., cov: 32)
  • Exomes 𝑓: 0.50 (178335 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 1.43
• Publications: 41 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=2.9413291E-5).
• BP6: Variant 14-21302571-A-G is Benign according to our data. Variant chr14-21302571-A-G is described in ClinVar as Benign. ClinVar VariationId is 99827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 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.574A>G	p.Lys192Glu	missense	Exon 5 of 25	NP_065099.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.574A>G	p.Lys192Glu	missense	Exon 5 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000557771.5	TSL:5	c.574A>G	p.Lys192Glu	missense	Exon 4 of 24	ENSP00000451219.1	G3V3F7
	RPGRIP1	ENST00000556336.5	TSL:5	c.574A>G	p.Lys192Glu	missense	Exon 4 of 21	ENSP00000450445.1	G3V236

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74340 AN: 151930 Hom.: 18303 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.470

GnomAD2 exomes AF: 0.503 AC: 100555 AN: 199846 AF XY: 0.508

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.327

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.502

GnomAD4 exome AF: 0.500 AC: 705005 AN: 1409746 Hom.: 178335 Cov.: 26 AF XY: 0.502 AC XY: 350608 AN XY: 697818

African (AFR) AF: 0.454 AC: 14736 AN: 32488

American (AMR) AF: 0.510 AC: 19917 AN: 39084

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 10431 AN: 25050

East Asian (EAS) AF: 0.307 AC: 11653 AN: 37994

South Asian (SAS) AF: 0.594 AC: 46809 AN: 78758

European-Finnish (FIN) AF: 0.544 AC: 27611 AN: 50764

Middle Eastern (MID) AF: 0.507 AC: 2868 AN: 5658

European-Non Finnish (NFE) AF: 0.502 AC: 542571 AN: 1081562

Other (OTH) AF: 0.487 AC: 28409 AN: 58388

GnomAD4 genome AF: 0.489 AC: 74409 AN: 152048 Hom.: 18322 Cov.: 32 AF XY: 0.492 AC XY: 36536 AN XY: 74312

African (AFR) AF: 0.461 AC: 19120 AN: 41460

American (AMR) AF: 0.494 AC: 7535 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1493 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1662 AN: 5164

South Asian (SAS) AF: 0.594 AC: 2868 AN: 4828

European-Finnish (FIN) AF: 0.524 AC: 5535 AN: 10570

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34610 AN: 67988

Other (OTH) AF: 0.471 AC: 995 AN: 2112

Alfa AF: 0.496 Hom.: 95589

Bravo AF: 0.478

TwinsUK AF: 0.502 AC: 1863

ALSPAC AF: 0.499 AC: 1923

ESP6500AA AF: 0.448 AC: 1697

ESP6500EA AF: 0.498 AC: 4112

ExAC AF: 0.467 AC: 55358

Asia WGS AF: 0.507 AC: 1763 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Cone-rod dystrophy 13 (2)
-	-	2	Leber congenital amaurosis 6 (2)
-	-	2	not provided (3)
-	-	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.9
DANN	Benign	0.56
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.000029	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.28	N
PhyloP100		1.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.091
ClinPred		0.0022	T
GERP RS		3.1
Varity_R		0.058
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6571751; hg19: chr14-21770730; COSMIC: COSV52846904;