14-21327790-G-C

Variant names:

• chr14-21327790-G-C
• rs35810926
• NM_020366.4:c.2878G>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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. 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
• Publications: 4 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 -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 VariationId is 534365.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	NM_020366.4	MANE Select	c.2878G>C	p.Ala960Pro	missense	Exon 18 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.1804G>C	p.Ala602Pro	missense	Exon 8 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.964G>C	p.Ala322Pro	missense	Exon 6 of 13	NP_001364878.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.2878G>C	p.Ala960Pro	missense	Exon 18 of 25	ENSP00000382895.2	Q96KN7-1
	RPGRIP1	ENST00000555587.5	TSL:1	c.1303G>C	p.Ala435Pro	missense	Exon 6 of 13	ENSP00000451262.1	G3V3I7
	RPGRIP1	ENST00000382933.8	TSL:1	c.856G>C	p.Ala286Pro	missense	Exon 5 of 12	ENSP00000372391.4	Q96KN7-4

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

GnomAD2 exomes AF: 0.00124 AC: 291 AN: 235550 AF XY: 0.000859

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 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

African (AFR) AF: 0.0169 AC: 552 AN: 32730

American (AMR) AF: 0.00101 AC: 42 AN: 41396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25150

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39526

South Asian (SAS) AF: 0.0000595 AC: 5 AN: 84022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53078

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5664

European-Non Finnish (NFE) AF: 0.0000870 AC: 96 AN: 1103724

Other (OTH) AF: 0.00106 AC: 63 AN: 59544

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

African (AFR) AF: 0.0151 AC: 628 AN: 41578

American (AMR) AF: 0.00164 AC: 25 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Cone-rod dystrophy 13 (2)
-	1	1	Leber congenital amaurosis 6 (2)
-	-	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.029
DANN	Benign	0.19
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L
PhyloP100		-1.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.27	T
Polyphen		0.0	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
Mutation Taster		=94/6	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: rs35810926; hg19: chr14-21795949;