rs138724933

Variant names:

• chr16-53611044-G-A
• rs138724933
• NM_015272.5:c.3624C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_015272.5(RPGRIP1L):​c.3624C>T​(p.Tyr1208Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,610,014 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: RPGRIP1L NM_015272.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 0.647
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 16-53611044-G-A is Benign according to our data. Variant chr16-53611044-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260608.
• BP7: Synonymous conserved (PhyloP=0.647 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.3624C>T	p.Tyr1208Tyr	synonymous	Exon 25 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.3522C>T	p.Tyr1174Tyr	synonymous	Exon 24 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.3486C>T	p.Tyr1162Tyr	synonymous	Exon 24 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.3624C>T	p.Tyr1208Tyr	synonymous	Exon 25 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3522C>T	p.Tyr1174Tyr	synonymous	Exon 24 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3486C>T	p.Tyr1162Tyr	synonymous	Exon 24 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 151800 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000853

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000475 AC: 119 AN: 250646 AF XY: 0.000524

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000750

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00109 AC: 1586 AN: 1458096 Hom.: 3 Cov.: 30 AF XY: 0.00108 AC XY: 782 AN XY: 725564

African (AFR) AF: 0.000269 AC: 9 AN: 33426

American (AMR) AF: 0.000537 AC: 24 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.000418 AC: 36 AN: 86206

European-Finnish (FIN) AF: 0.0000566 AC: 3 AN: 52958

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5758

European-Non Finnish (NFE) AF: 0.00133 AC: 1480 AN: 1108986

Other (OTH) AF: 0.000498 AC: 30 AN: 60266

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151918 Hom.: 0 Cov.: 32 AF XY: 0.000674 AC XY: 50 AN XY: 74208

African (AFR) AF: 0.000169 AC: 7 AN: 41428

American (AMR) AF: 0.000852 AC: 13 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000417 AC: 2 AN: 4796

European-Finnish (FIN) AF: 0.000381 AC: 4 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00102 AC: 69 AN: 67972

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000757 Hom.: 0

Bravo AF: 0.000574

EpiCase AF: 0.00109

EpiControl AF: 0.000712

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Joubert syndrome (1)
-	1	-	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	1	-	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.6
DANN	Benign	0.45
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs138724933; hg19: chr16-53644956; COSMIC: COSV104383251;