chr14-21294686-T-A

Position:

chr14-21294686-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020366.4(RPGRIP1):c.95T>A(p.Met32Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,613,328 control chromosomes in the GnomAD database, including 5 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M32V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0022 ( 5 hom. )

Consequence

RPGRIP1
NM_020366.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:7

Conservation

PhyloP100: 0.184

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009699613).

BP6

Variant 14-21294686-T-A is Benign according to our data. Variant chr14-21294686-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195356.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=5}. Variant chr14-21294686-T-A is described in Lovd as [Benign]. Variant chr14-21294686-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00137 (208/152208) while in subpopulation NFE AF= 0.0025 (170/68010). AF 95% confidence interval is 0.00219. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4 linkuse as main transcript	c.95T>A	p.Met32Lys	missense_variant	3/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7 linkuse as main transcript	c.95T>A	p.Met32Lys	missense_variant	3/25	1	NM_020366.4	P2	Q96KN7-1
RPGRIP1	ENST00000557771.5 linkuse as main transcript	c.95T>A	p.Met32Lys	missense_variant	2/24	5		A2
RPGRIP1	ENST00000556336.5 linkuse as main transcript	c.95T>A	p.Met32Lys	missense_variant	2/21	5

Frequencies

GnomAD3 genomes

AF:

0.00137

AC:

208

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00128

AC:

319

AN:

248600

Hom.:

AF XY:

0.00125

AC XY:

168

AN XY:

134900

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.000204

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000790

Gnomad FIN exome

AF:

0.000325

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.00216

AC:

3152

AN:

1461120

Hom.:

Cov.:

AF XY:

0.00210

AC XY:

1523

AN XY:

726886

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000789

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00268

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.00137

AC:

208

AN:

152208

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000984

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00134

AC:

ESP6500EA

AF:

0.00281

AC:

ExAC

AF:

0.00159

AC:

192

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	RPGRIP1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2014	- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Cone-rod dystrophy 13

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Leber congenital amaurosis 6

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.075

T;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.58

T;T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

.;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

D;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.020

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

0.17

.;.;B

Vest4

0.44

MVP

0.63

MPC

0.11

ClinPred

0.011

GERP RS

-0.55

Varity_R

0.41

gMVP

0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over