chr14-21327790-G-C

Position:

• chr14-21327790-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_020366.4(RPGRIP1):​c.2878G>C​(p.Ala960Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000898 in 1,597,138 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. A960T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (8 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -1.23

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036054552).
• BP6: Variant 14-21327790-G-C is Benign according to our data. Variant chr14-21327790-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 534365.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr14-21327790-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00438 (667/152304) while in subpopulation AFR AF= 0.0151 (628/41578). AF 95% confidence interval is 0.0141. There are 8 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1	NM_020366.4	c.2878G>C	p.Ala960Pro	missense_variant	18/25	ENST00000400017.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.2878G>C	p.Ala960Pro	missense_variant	18/25	1	NM_020366.4	P2

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00124 AC: 291 AN: 235550 Hom.: 2 AF XY: 0.000859 AC XY: 110 AN XY: 128002

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000741

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000341

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000831

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000531 AC: 767 AN: 1444834 Hom.: 8 Cov.: 30 AF XY: 0.000463 AC XY: 332 AN XY: 717520

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000595

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000870

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152304 Hom.: 8 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74474

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.00500

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0137 AC: 52

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00140 AC: 169

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cone-rod dystrophy 13 Uncertain:1 Benign: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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Leber congenital amaurosis 6 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.029
DANN	Benign	0.19
DEOGEN2	Benign	0.012	T;T;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.44	T;T;T;T;T
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;B;B;B
Vest4		0.15
MVP		0.39
MPC		0.085
ClinPred		0.0040	T
GERP RS		-4.8
Varity_R		0.076
gMVP		0.26

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

Other links and lift over

dbSNP: rs35810926; hg19: chr14-21795949;