rs61747071

Variant names:

• chr16-53686524-C-T
• rs61747071
• NM_015272.5:c.685G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-53686524-C-T
• chr16-53686524-C-A
• chr16-53686524-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.685G>A​(p.Ala229Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0341 in 1,613,474 control chromosomes in the GnomAD database, including 1,418 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 0.049 (293 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1125 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:3
• Conservation: PhyloP100: -0.0220
• Publications: 40 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=0.004353553).
• BP6: Variant 16-53686524-C-T is Benign according to our data. Variant chr16-53686524-C-T is described in ClinVar as Benign. ClinVar VariationId is 1078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.685G>A	p.Ala229Thr	missense	Exon 6 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.685G>A	p.Ala229Thr	missense	Exon 6 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.685G>A	p.Ala229Thr	missense	Exon 6 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.685G>A	p.Ala229Thr	missense	Exon 6 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.685G>A	p.Ala229Thr	missense	Exon 6 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.685G>A	p.Ala229Thr	missense	Exon 6 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7441 AN: 152014 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0209

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0794

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0657

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0576

GnomAD2 exomes AF: 0.0356 AC: 8949 AN: 251116 AF XY: 0.0363

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0841

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00869

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0361

GnomAD4 exome AF: 0.0325 AC: 47508 AN: 1461340 Hom.: 1125 Cov.: 31 AF XY: 0.0333 AC XY: 24235 AN XY: 726978

African (AFR) AF: 0.107 AC: 3575 AN: 33448

American (AMR) AF: 0.0223 AC: 995 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 2203 AN: 26122

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39656

South Asian (SAS) AF: 0.0680 AC: 5867 AN: 86244

European-Finnish (FIN) AF: 0.00927 AC: 495 AN: 53394

Middle Eastern (MID) AF: 0.0790 AC: 455 AN: 5760

European-Non Finnish (NFE) AF: 0.0284 AC: 31620 AN: 1111652

Other (OTH) AF: 0.0379 AC: 2290 AN: 60372

GnomAD4 genome AF: 0.0490 AC: 7448 AN: 152134 Hom.: 293 Cov.: 32 AF XY: 0.0470 AC XY: 3497 AN XY: 74392

African (AFR) AF: 0.105 AC: 4343 AN: 41492

American (AMR) AF: 0.0285 AC: 435 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0794 AC: 275 AN: 3462

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0666 AC: 321 AN: 4818

European-Finnish (FIN) AF: 0.00698 AC: 74 AN: 10598

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0271 AC: 1841 AN: 67998

Other (OTH) AF: 0.0570 AC: 120 AN: 2106

Alfa AF: 0.0381 Hom.: 355

Bravo AF: 0.0519

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0296 AC: 114

ESP6500AA AF: 0.101 AC: 443

ESP6500EA AF: 0.0328 AC: 282

ExAC AF: 0.0374 AC: 4547

Asia WGS AF: 0.0360 AC: 125 AN: 3476

EpiCase AF: 0.0334

EpiControl AF: 0.0349

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
1	-	1	Joubert syndrome (2)
-	-	2	Joubert syndrome 7 (3)
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Meckel syndrome, type 5 (1)
-	-	1	Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)
-	-	-	Nephronophthisis (1)
-	-	-	Retinitis pigmentosa in ciliopathies, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.022
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.18
Sift	Benign	0.47	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.070
ClinPred		0.0045	T
GERP RS		2.7
Varity_R		0.054
gMVP		0.19
Mutation Taster		=100/0	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: rs61747071; hg19: chr16-53720436;