chr14-21301034-C-G

Position:

• chr14-21301034-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020366.4(RPGRIP1):​c.287C>G​(p.Pro96Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P96Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RPGRIP1 NM_020366.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049742967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGRIP1	NM_020366.4	c.287C>G	p.Pro96Arg	missense_variant	4/25	ENST00000400017.7	NP_065099.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGRIP1	ENST00000400017.7	c.287C>G	p.Pro96Arg	missense_variant	4/25	1	NM_020366.4	ENSP00000382895	P2
RPGRIP1	ENST00000557771.5	c.287C>G	p.Pro96Arg	missense_variant	3/24	5		ENSP00000451219	A2
RPGRIP1	ENST00000556336.5	c.287C>G	p.Pro96Arg	missense_variant	3/21	5		ENSP00000450445

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000412 AC: 1 AN: 242586 Hom.: 0 AF XY: 0.00000753 AC XY: 1 AN XY: 132852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000924

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460116 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726328

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000833 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.8
DANN	Benign	0.61
DEOGEN2	Benign	0.0033	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.49	T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.76	N;N;N
REVEL	Benign	0.026
Sift	Benign	0.61	T;T;T
Sift4G	Benign	0.56	T;T;T
Polyphen		0.20	.;.;B
Vest4		0.072
MutPred		0.30		Gain of MoRF binding (P = 3e-04);Gain of MoRF binding (P = 3e-04);Gain of MoRF binding (P = 3e-04);
MVP		0.28
MPC		0.071
ClinPred		0.060	T
GERP RS		-0.43
Varity_R		0.025
gMVP		0.089

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: rs1040904; hg19: chr14-21769193;