rs200510462

Variant names:

• chr14-21294686-T-A
• rs200510462
• NM_020366.4:c.95T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-21294686-T-A
• chr14-21294686-T-G

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.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. 16/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:7
• Conservation: PhyloP100: 0.184
• Publications: 3 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 -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 VariationId is 195356.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.95T>A	p.Met32Lys	missense	Exon 3 of 25	NP_065099.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.95T>A	p.Met32Lys	missense	Exon 3 of 25	ENSP00000382895.2
	RPGRIP1	ENST00000557771.5	TSL:5	c.95T>A	p.Met32Lys	missense	Exon 2 of 24	ENSP00000451219.1
	RPGRIP1	ENST00000556336.5	TSL:5	c.95T>A	p.Met32Lys	missense	Exon 2 of 21	ENSP00000450445.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 152090 Hom.: 0 Cov.: 30

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

GnomAD2 exomes AF: 0.00128 AC: 319 AN: 248600 AF XY: 0.00125

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 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.: 5 Cov.: 31 AF XY: 0.00210 AC XY: 1523 AN XY: 726886

African (AFR) AF: 0.000359 AC: 12 AN: 33450

American (AMR) AF: 0.000157 AC: 7 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000789 AC: 68 AN: 86136

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53384

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00268 AC: 2974 AN: 1111640

Other (OTH) AF: 0.00101 AC: 61 AN: 60350

GnomAD4 genome AF: 0.00137 AC: 208 AN: 152208 Hom.: 0 Cov.: 30 AF XY: 0.00113 AC XY: 84 AN XY: 74428

African (AFR) AF: 0.000385 AC: 16 AN: 41542

American (AMR) AF: 0.000984 AC: 15 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00250 AC: 170 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00210 Hom.: 1

Bravo AF: 0.00133

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00134 AC: 5

ESP6500EA AF: 0.00281 AC: 23

ExAC AF: 0.00159 AC: 192

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00225

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	Cone-rod dystrophy 13 (2)
-	1	1	Leber congenital amaurosis 6 (2)
-	1	1	Leber congenital amaurosis 6;C2750720:Cone-rod dystrophy 13 (2)
-	-	1	not specified (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.18
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.17	B
Vest4		0.44
MVP		0.63
MPC		0.11
ClinPred		0.011	T
GERP RS		-0.55
Varity_R		0.41
gMVP		0.25
Mutation Taster		=99/1	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: rs200510462; hg19: chr14-21762845;