rs28664100

Variant names:

• chr14-21343021-C-T
• rs28664100
• NM_020366.4:c.3340-15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020366.4(RPGRIP1):​c.3340-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00915 in 1,604,446 control chromosomes in the GnomAD database, including 1,170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (625 hom., cov: 31)
  • Exomes 𝑓: 0.0050 (545 hom.)
• Consequence: RPGRIP1 NM_020366.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.814
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-21343021-C-T is Benign according to our data. Variant chr14-21343021-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

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.3340-15C>T		intron	N/A	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2266-15C>T		intron	N/A	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1426-15C>T		intron	N/A	NP_001364878.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1	ENST00000400017.7	TSL:1 MANE Select	c.3340-15C>T		intron	N/A	ENSP00000382895.2
	RPGRIP1	ENST00000555587.5	TSL:1	c.1765-15C>T		intron	N/A	ENSP00000451262.1
	RPGRIP1	ENST00000382933.8	TSL:1	c.1318-15C>T		intron	N/A	ENSP00000372391.4

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7446 AN: 152096 Hom.: 621 Cov.: 31

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0127 AC: 3135 AN: 246842 AF XY: 0.00941

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.00899

Gnomad ASJ exome AF: 0.000905

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000472

Gnomad OTH exome AF: 0.00802

GnomAD4 exome AF: 0.00497 AC: 7212 AN: 1452232 Hom.: 545 Cov.: 28 AF XY: 0.00424 AC XY: 3067 AN XY: 722686

African (AFR) AF: 0.171 AC: 5657 AN: 33000

American (AMR) AF: 0.0102 AC: 449 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 44 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.000386 AC: 33 AN: 85478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00942 AC: 54 AN: 5730

European-Non Finnish (NFE) AF: 0.000249 AC: 275 AN: 1105164

Other (OTH) AF: 0.0117 AC: 700 AN: 60006

GnomAD4 genome AF: 0.0491 AC: 7471 AN: 152214 Hom.: 625 Cov.: 31 AF XY: 0.0473 AC XY: 3522 AN XY: 74430

African (AFR) AF: 0.170 AC: 7039 AN: 41488

American (AMR) AF: 0.0198 AC: 303 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68018

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0566 Hom.: 364

Bravo AF: 0.0566

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.6
DANN	Benign	0.69
PhyloP100		-0.81
Mutation Taster		=100/0	polymorphism (auto)

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: rs28664100; hg19: chr14-21811180;