rs2111119

Variant names:

• chr16-53637842-C-T
• rs2111119
• NM_015272.5:c.3073G>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.3073G>A​(p.Gly1025Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,611,706 control chromosomes in the GnomAD database, including 9,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1140 hom., cov: 32)
  • Exomes 𝑓: 0.095 (8103 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.51
• Publications: 37 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 (MetaRNN=0.004034281).
• BP6: Variant 16-53637842-C-T is Benign according to our data. Variant chr16-53637842-C-T is described in ClinVar as Benign. ClinVar VariationId is 126277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 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.3073G>A	p.Gly1025Ser	missense	Exon 21 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.2971G>A	p.Gly991Ser	missense	Exon 20 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.3073G>A	p.Gly1025Ser	missense	Exon 21 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.3073G>A	p.Gly1025Ser	missense	Exon 21 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2971G>A	p.Gly991Ser	missense	Exon 20 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3073G>A	p.Gly1025Ser	missense	Exon 21 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16938 AN: 151960 Hom.: 1134 Cov.: 32

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.0835

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.112 AC: 28086 AN: 250566 AF XY: 0.110

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0904

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0809

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0954 AC: 139258 AN: 1459628 Hom.: 8103 Cov.: 32 AF XY: 0.0961 AC XY: 69800 AN XY: 726206

African (AFR) AF: 0.155 AC: 5191 AN: 33404

American (AMR) AF: 0.0886 AC: 3960 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3756 AN: 26102

East Asian (EAS) AF: 0.280 AC: 11098 AN: 39592

South Asian (SAS) AF: 0.137 AC: 11842 AN: 86212

European-Finnish (FIN) AF: 0.0550 AC: 2904 AN: 52842

Middle Eastern (MID) AF: 0.110 AC: 633 AN: 5758

European-Non Finnish (NFE) AF: 0.0838 AC: 93104 AN: 1110730

Other (OTH) AF: 0.112 AC: 6770 AN: 60310

GnomAD4 genome AF: 0.112 AC: 16959 AN: 152078 Hom.: 1140 Cov.: 32 AF XY: 0.110 AC XY: 8162 AN XY: 74310

African (AFR) AF: 0.158 AC: 6545 AN: 41478

American (AMR) AF: 0.0838 AC: 1280 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 470 AN: 3462

East Asian (EAS) AF: 0.309 AC: 1594 AN: 5158

South Asian (SAS) AF: 0.143 AC: 689 AN: 4822

European-Finnish (FIN) AF: 0.0482 AC: 510 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0812 AC: 5519 AN: 67982

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.0972 Hom.: 3979

Bravo AF: 0.117

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.157 AC: 688

ESP6500EA AF: 0.0865 AC: 744

ExAC AF: 0.114 AC: 13893

Asia WGS AF: 0.232 AC: 804 AN: 3476

EpiCase AF: 0.0855

EpiControl AF: 0.0860

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.19
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N
PhyloP100		1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.21
Sift	Benign	1.0	T
Sift4G	Benign	0.82	T
Polyphen		0.0	B
Vest4		0.029
MPC		0.072
ClinPred		0.00058	T
GERP RS		3.0
Varity_R		0.030
gMVP		0.12
Mutation Taster		=98/2	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: rs2111119; hg19: chr16-53671754; COSMIC: COSV50903572;