rs143863631

Variant names:

• chr16-53652877-C-T
• rs143863631
• NM_015272.5:c.1810G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.1810G>A​(p.Glu604Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,612,524 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E604E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (7 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 5.54
• Publications: 8 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):

• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019843072).
• BP6: Variant 16-53652877-C-T is Benign according to our data. Variant chr16-53652877-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289611.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000407 (62/152270) while in subpopulation EAS AF = 0.00425 (22/5182). AF 95% confidence interval is 0.00287. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.1810G>A	p.Glu604Lys	missense	Exon 15 of 27	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.1810G>A	p.Glu604Lys	missense	Exon 15 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.1810G>A	p.Glu604Lys	missense	Exon 15 of 26	NP_001295263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.1810G>A	p.Glu604Lys	missense	Exon 15 of 27	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.1810G>A	p.Glu604Lys	missense	Exon 15 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.1810G>A	p.Glu604Lys	missense	Exon 15 of 26	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000404 AC: 101 AN: 249866 AF XY: 0.000356

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00380

Gnomad EAS exome AF: 0.00180

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000493

GnomAD4 exome AF: 0.000562 AC: 821 AN: 1460254 Hom.: 7 Cov.: 32 AF XY: 0.000536 AC XY: 389 AN XY: 726314

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.000135 AC: 6 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 116 AN: 26062

East Asian (EAS) AF: 0.0120 AC: 477 AN: 39674

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85864

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53398

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000155 AC: 172 AN: 1111414

Other (OTH) AF: 0.000663 AC: 40 AN: 60318

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74450

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00425 AC: 22 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000295

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Joubert syndrome (1)
-	1	-	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	1	-	Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5435651:COACH syndrome 1 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	1	-	Nephronophthisis 8 (1)
-	1	-	RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.77
MPC		0.44
ClinPred		0.12	T
GERP RS		4.5
Varity_R		0.68
gMVP		0.86
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143863631; hg19: chr16-53686789; COSMIC: COSV50908535; COSMIC: COSV50908535;