16-53649037-C-T

Variant names:

• chr16-53649037-C-T
• rs2302677
• NM_015272.5:c.2231G>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.2231G>A​(p.Arg744Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,796 control chromosomes in the GnomAD database, including 1,789 homozygotes. In-silico tool predicts 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. R744L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.032 (161 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1628 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 2.43
• 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):

• 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=0.0016984642).
• BP6: Variant 16-53649037-C-T is Benign according to our data. Variant chr16-53649037-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 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.2231G>A	p.Arg744Gln	missense	Exon 16 of 27	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.2231G>A	p.Arg744Gln	missense	Exon 16 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.2231G>A	p.Arg744Gln	missense	Exon 16 of 26	NP_001295263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.2231G>A	p.Arg744Gln	missense	Exon 16 of 27	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2231G>A	p.Arg744Gln	missense	Exon 16 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.2231G>A	p.Arg744Gln	missense	Exon 16 of 26	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 4793 AN: 152112 Hom.: 154 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0337

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0946

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0350

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0462 AC: 11606 AN: 251400 AF XY: 0.0500

Gnomad AFR exome AF: 0.00861

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0380

Gnomad EAS exome AF: 0.163

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0478

GnomAD4 exome AF: 0.0386 AC: 56349 AN: 1461566 Hom.: 1628 Cov.: 31 AF XY: 0.0407 AC XY: 29559 AN XY: 727130

African (AFR) AF: 0.0108 AC: 360 AN: 33472

American (AMR) AF: 0.0245 AC: 1096 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 966 AN: 26130

East Asian (EAS) AF: 0.133 AC: 5291 AN: 39678

South Asian (SAS) AF: 0.0921 AC: 7941 AN: 86248

European-Finnish (FIN) AF: 0.00799 AC: 427 AN: 53416

Middle Eastern (MID) AF: 0.120 AC: 691 AN: 5762

European-Non Finnish (NFE) AF: 0.0331 AC: 36849 AN: 1111754

Other (OTH) AF: 0.0452 AC: 2728 AN: 60382

GnomAD4 genome AF: 0.0316 AC: 4804 AN: 152230 Hom.: 161 Cov.: 32 AF XY: 0.0324 AC XY: 2415 AN XY: 74438

African (AFR) AF: 0.0101 AC: 418 AN: 41534

American (AMR) AF: 0.0319 AC: 488 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 117 AN: 3468

East Asian (EAS) AF: 0.136 AC: 704 AN: 5178

South Asian (SAS) AF: 0.0942 AC: 454 AN: 4818

European-Finnish (FIN) AF: 0.00688 AC: 73 AN: 10604

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0350 AC: 2380 AN: 68020

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0363 Hom.: 665

Bravo AF: 0.0313

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0337 AC: 130

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.0327 AC: 281

ExAC AF: 0.0463 AC: 5619

Asia WGS AF: 0.0990 AC: 343 AN: 3478

EpiCase AF: 0.0419

EpiControl AF: 0.0445

ClinVar

ClinVar submissions as Germline

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	Kidney disorder (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.32
Sift	Benign	0.040	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.28
MPC		0.43
ClinPred		0.019	T
GERP RS		6.1
Varity_R		0.14
gMVP		0.59
Mutation Taster		=99/1	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: rs2302677; hg19: chr16-53682949; COSMIC: COSV50909319; COSMIC: COSV50909319;