rs3213758

Variant names:

• chr16-53605526-C-T
• rs3213758
• NM_015272.5:c.3790G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-53605526-C-T
• chr16-53605526-C-G

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.3790G>A​(p.Asp1264Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0611 in 1,613,892 control chromosomes in the GnomAD database, including 4,510 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1264S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.051 (395 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4115 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.23
• Publications: 50 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=0.0065824986).
• BP6: Variant 16-53605526-C-T is Benign according to our data. Variant chr16-53605526-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.29 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.3790G>A	p.Asp1264Asn	missense	Exon 26 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.3688G>A	p.Asp1230Asn	missense	Exon 25 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.3652G>A	p.Asp1218Asn	missense	Exon 25 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.3790G>A	p.Asp1264Asn	missense	Exon 26 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3688G>A	p.Asp1230Asn	missense	Exon 25 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3652G>A	p.Asp1218Asn	missense	Exon 25 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.0510 AC: 7755 AN: 152082 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0514

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.0763

Gnomad FIN AF: 0.0414

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0551

GnomAD2 exomes AF: 0.0729 AC: 18333 AN: 251334 AF XY: 0.0714

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0675

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.313

Gnomad FIN exome AF: 0.0442

Gnomad NFE exome AF: 0.0532

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0622 AC: 90897 AN: 1461694 Hom.: 4115 Cov.: 32 AF XY: 0.0622 AC XY: 45237 AN XY: 727180

African (AFR) AF: 0.00968 AC: 324 AN: 33480

American (AMR) AF: 0.0641 AC: 2869 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 1560 AN: 26134

East Asian (EAS) AF: 0.278 AC: 11043 AN: 39700

South Asian (SAS) AF: 0.0693 AC: 5977 AN: 86258

European-Finnish (FIN) AF: 0.0457 AC: 2440 AN: 53418

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5766

European-Non Finnish (NFE) AF: 0.0560 AC: 62261 AN: 1111824

Other (OTH) AF: 0.0707 AC: 4270 AN: 60390

GnomAD4 genome AF: 0.0510 AC: 7756 AN: 152198 Hom.: 395 Cov.: 32 AF XY: 0.0515 AC XY: 3830 AN XY: 74410

African (AFR) AF: 0.0128 AC: 531 AN: 41550

American (AMR) AF: 0.0517 AC: 791 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3468

East Asian (EAS) AF: 0.302 AC: 1555 AN: 5148

South Asian (SAS) AF: 0.0757 AC: 364 AN: 4808

European-Finnish (FIN) AF: 0.0414 AC: 439 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0545 AC: 3705 AN: 68006

Other (OTH) AF: 0.0569 AC: 120 AN: 2108

Alfa AF: 0.0579 Hom.: 1793

Bravo AF: 0.0521

TwinsUK AF: 0.0539 AC: 200

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0551 AC: 474

ExAC AF: 0.0728 AC: 8838

Asia WGS AF: 0.188 AC: 654 AN: 3478

EpiCase AF: 0.0525

EpiControl AF: 0.0514

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Joubert syndrome 7 (2)
-	-	2	Meckel syndrome, type 5 (2)
-	-	2	not provided (2)
-	-	1	Joubert syndrome (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.24	T
Sift4G	Benign	0.070	T
Polyphen		0.96	D
Vest4		0.083
MPC		0.071
ClinPred		0.0019	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.43
Mutation Taster		=95/5	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: rs3213758; hg19: chr16-53639438; COSMIC: COSV50903544;