14-21345126-C-T

Variant names:

• chr14-21345126-C-T
• rs34116882
• NM_020366.4:c.3546C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_020366.4(RPGRIP1):​c.3546C>T​(p.Asp1182Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,611,240 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.022 (396 hom.)
• Consequence: RPGRIP1 NM_020366.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0360
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 14-21345126-C-T is Benign according to our data. Variant chr14-21345126-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 99820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.036 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0154 (2344/152256) while in subpopulation NFE AF = 0.0249 (1692/68014). AF 95% confidence interval is 0.0239. There are 24 homozygotes in GnomAd4. There are 1103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.3546C>T	p.Asp1182Asp	synonymous	Exon 23 of 25	NP_065099.3
	RPGRIP1	NM_001377948.1		c.2472C>T	p.Asp824Asp	synonymous	Exon 13 of 15	NP_001364877.1
	RPGRIP1	NM_001377949.1		c.1632C>T	p.Asp544Asp	synonymous	Exon 11 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.3546C>T	p.Asp1182Asp	synonymous	Exon 23 of 25	ENSP00000382895.2
	RPGRIP1	ENST00000555587.5	TSL:1	c.1971C>T	p.Asp657Asp	synonymous	Exon 11 of 13	ENSP00000451262.1
	RPGRIP1	ENST00000382933.8	TSL:1	c.1524C>T	p.Asp508Asp	synonymous	Exon 10 of 12	ENSP00000372391.4

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2344 AN: 152138 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00937

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0249

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.0168 AC: 4173 AN: 249058 AF XY: 0.0167

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00551

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0273

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0222 AC: 32421 AN: 1458984 Hom.: 396 Cov.: 29 AF XY: 0.0218 AC XY: 15798 AN XY: 725938

African (AFR) AF: 0.00335 AC: 112 AN: 33436

American (AMR) AF: 0.00550 AC: 246 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 347 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00198 AC: 171 AN: 86206

European-Finnish (FIN) AF: 0.0275 AC: 1467 AN: 53368

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5764

European-Non Finnish (NFE) AF: 0.0262 AC: 29036 AN: 1109434

Other (OTH) AF: 0.0170 AC: 1026 AN: 60280

GnomAD4 genome AF: 0.0154 AC: 2344 AN: 152256 Hom.: 24 Cov.: 32 AF XY: 0.0148 AC XY: 1103 AN XY: 74446

African (AFR) AF: 0.00363 AC: 151 AN: 41544

American (AMR) AF: 0.00936 AC: 143 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0249 AC: 1692 AN: 68014

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.0234 Hom.: 83

Bravo AF: 0.0141

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0212

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	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	-0.40
CADD	Benign	5.4
DANN	Benign	0.56
PhyloP100		0.036
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34116882; hg19: chr14-21813285;