NM_020366.4:c.1767G>T

Variant names:

• chr14-21324622-G-T
• rs34067949
• NM_020366.4:c.1767G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020366.4(RPGRIP1):​c.1767G>T​(p.Gln589His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00486 in 1,612,740 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (20 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.99
• Publications: 13 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: 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=0.010454863).
• BP6: Variant 14-21324622-G-T is Benign according to our data. Variant chr14-21324622-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00343 (522/152256) while in subpopulation AMR AF = 0.00635 (97/15286). AF 95% confidence interval is 0.00532. There are 3 homozygotes in GnomAd4. There are 230 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.1767G>T	p.Gln589His	missense	Exon 15 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.693G>T	p.Gln231His	missense	Exon 5 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.693G>T	p.Gln231His	missense	Exon 5 of 13	NP_001364878.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.1767G>T	p.Gln589His	missense	Exon 15 of 25	ENSP00000382895.2
	RPGRIP1	ENST00000555587.5	TSL:1	c.192G>T	p.Gln64His	missense	Exon 3 of 13	ENSP00000451262.1
	RPGRIP1	ENST00000554303.1	TSL:1	c.153G>T	p.Gln51His	missense	Exon 3 of 3	ENSP00000450426.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 522 AN: 152138 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00511

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00287 AC: 713 AN: 248084 AF XY: 0.00296

Gnomad AFR exome AF: 0.00116

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00499

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00501 AC: 7313 AN: 1460484 Hom.: 20 Cov.: 30 AF XY: 0.00486 AC XY: 3531 AN XY: 726622

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.00210 AC: 94 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86256

European-Finnish (FIN) AF: 0.00136 AC: 71 AN: 52332

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.00610 AC: 6777 AN: 1111724

Other (OTH) AF: 0.00424 AC: 256 AN: 60366

GnomAD4 genome AF: 0.00343 AC: 522 AN: 152256 Hom.: 3 Cov.: 32 AF XY: 0.00309 AC XY: 230 AN XY: 74442

African (AFR) AF: 0.00130 AC: 54 AN: 41550

American (AMR) AF: 0.00635 AC: 97 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10594

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00512 AC: 348 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00435 Hom.: 5

Bravo AF: 0.00343

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.00532 AC: 44

ExAC AF: 0.00304 AC: 368

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00556

EpiControl AF: 0.00569

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.21	D
PhyloP100		2.0
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.99	D
Vest4		0.78
MutPred		0.61		Loss of ubiquitination at K591 (P = 0.074)
MVP		0.93
MPC		0.32
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.48
gMVP		0.66
Mutation Taster		=80/20	polymorphism

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: rs34067949; hg19: chr14-21792781; COSMIC: COSV105068591; COSMIC: COSV105068591;