rs139503476

Variant names:

• chr16-53645665-A-T
• rs139503476
• NM_015272.5:c.2643T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015272.5(RPGRIP1L):​c.2643T>A​(p.Asn881Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,614,046 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 1.07
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009774983).
• BP6: Variant 16-53645665-A-T is Benign according to our data. Variant chr16-53645665-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194767.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00152 (232/152308) while in subpopulation AFR AF = 0.00532 (221/41566). AF 95% confidence interval is 0.00474. There are 1 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2643T>A	p.Asn881Lys	missense	Exon 17 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.2643T>A	p.Asn881Lys	missense	Exon 17 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.2643T>A	p.Asn881Lys	missense	Exon 17 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.2643T>A	p.Asn881Lys	missense	Exon 17 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2643T>A	p.Asn881Lys	missense	Exon 17 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.2643T>A	p.Asn881Lys	missense	Exon 17 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.00148 AC: 226 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000430 AC: 108 AN: 250874 AF XY: 0.000310

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1461738 Hom.: 1 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727170

African (AFR) AF: 0.00544 AC: 182 AN: 33478

American (AMR) AF: 0.000403 AC: 18 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111954

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74482

African (AFR) AF: 0.00532 AC: 221 AN: 41566

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000361 Hom.: 0

Bravo AF: 0.00171

ESP6500AA AF: 0.00637 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)
-	-	1	not specified (1)
-	-	1	RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.3
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.18
Sift	Benign	0.27	T
Sift4G	Benign	0.92	T
Polyphen		0.0050	B
Vest4		0.24
MutPred		0.65		Gain of methylation at N881 (P = 0.003)
MVP		0.55
MPC		0.083
ClinPred		0.0014	T
GERP RS		3.2
Varity_R		0.085
gMVP		0.38
Mutation Taster		=99/1	polymorphism

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: rs139503476; hg19: chr16-53679577;