rs4784319

Variant names:

• chr16-53602021-A-T
• rs4784319
• NM_015272.5:c.*55T>A

Variant summary

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

The NM_015272.5(RPGRIP1L):​c.*55T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 1,003,926 control chromosomes in the GnomAD database, including 57,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12810 hom., cov: 32)
  • Exomes 𝑓: 0.31 (44733 hom.)
• Consequence: RPGRIP1L NM_015272.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.401
• Publications: 15 publications found

Genes affected

RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]

RPGRIP1L Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
• Meckel syndrome, type 5

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Joubert syndrome 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with renal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR 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 16-53602021-A-T is Benign according to our data. Variant chr16-53602021-A-T is described in ClinVar as Benign. ClinVar VariationId is 319645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015272.5. 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
	RPGRIP1L	NM_015272.5	MANE Select	c.*55T>A		3_prime_UTR	Exon 27 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.*55T>A		3_prime_UTR	Exon 26 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.*55T>A		3_prime_UTR	Exon 26 of 26	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.*55T>A		3_prime_UTR	Exon 27 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.*55T>A		3_prime_UTR	Exon 26 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.*55T>A		3_prime_UTR	Exon 26 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57861 AN: 151944 Hom.: 12770 Cov.: 32

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.308 AC: 262463 AN: 851864 Hom.: 44733 Cov.: 11 AF XY: 0.314 AC XY: 139949 AN XY: 445450

African (AFR) AF: 0.601 AC: 12452 AN: 20718

American (AMR) AF: 0.226 AC: 9192 AN: 40728

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 8285 AN: 21910

East Asian (EAS) AF: 0.547 AC: 19352 AN: 35352

South Asian (SAS) AF: 0.428 AC: 30632 AN: 71502

European-Finnish (FIN) AF: 0.183 AC: 9342 AN: 51148

Middle Eastern (MID) AF: 0.445 AC: 1983 AN: 4458

European-Non Finnish (NFE) AF: 0.278 AC: 157494 AN: 566118

Other (OTH) AF: 0.344 AC: 13731 AN: 39930

GnomAD4 genome AF: 0.381 AC: 57959 AN: 152062 Hom.: 12810 Cov.: 32 AF XY: 0.376 AC XY: 27976 AN XY: 74310

African (AFR) AF: 0.598 AC: 24805 AN: 41472

American (AMR) AF: 0.287 AC: 4387 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.585 AC: 3015 AN: 5154

South Asian (SAS) AF: 0.428 AC: 2060 AN: 4814

European-Finnish (FIN) AF: 0.178 AC: 1881 AN: 10594

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.287 AC: 19495 AN: 67964

Other (OTH) AF: 0.385 AC: 813 AN: 2112

Alfa AF: 0.331 Hom.: 1178

Bravo AF: 0.395

Asia WGS AF: 0.510 AC: 1777 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Joubert syndrome 7 (2)
-	-	2	Meckel syndrome, type 5 (2)
-	-	2	not provided (2)
-	-	1	Nephronophthisis 8 (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		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4784319; hg19: chr16-53635933; COSMIC: COSV50903475; COSMIC: COSV50903475;