NM_015272.5:c.1340T>C

Variant names:

• chr16-53658782-A-G
• rs138155747
• NM_015272.5:c.1340T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.1340T>C​(p.Leu447Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,593,768 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L447L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (20 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 3.41
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066491365).
• BP6: Variant 16-53658782-A-G is Benign according to our data. Variant chr16-53658782-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193900.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00317 (483/152292) while in subpopulation NFE AF = 0.00497 (338/68010). AF 95% confidence interval is 0.00453. There are 0 homozygotes in GnomAd4. There are 229 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

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.1340T>C	p.Leu447Ser	missense	Exon 11 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.1340T>C	p.Leu447Ser	missense	Exon 11 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.1340T>C	p.Leu447Ser	missense	Exon 11 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.1340T>C	p.Leu447Ser	missense	Exon 11 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.1340T>C	p.Leu447Ser	missense	Exon 11 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.1340T>C	p.Leu447Ser	missense	Exon 11 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 483 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00310 AC: 728 AN: 234860 AF XY: 0.00314

Gnomad AFR exome AF: 0.000589

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00797

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00432 AC: 6225 AN: 1441476 Hom.: 20 Cov.: 28 AF XY: 0.00425 AC XY: 3049 AN XY: 716664

African (AFR) AF: 0.000482 AC: 16 AN: 33214

American (AMR) AF: 0.00135 AC: 58 AN: 43114

Ashkenazi Jewish (ASJ) AF: 0.00244 AC: 63 AN: 25816

East Asian (EAS) AF: 0.00 AC: 0 AN: 39444

South Asian (SAS) AF: 0.000154 AC: 13 AN: 84586

European-Finnish (FIN) AF: 0.00873 AC: 459 AN: 52594

Middle Eastern (MID) AF: 0.000882 AC: 5 AN: 5672

European-Non Finnish (NFE) AF: 0.00489 AC: 5371 AN: 1097362

Other (OTH) AF: 0.00402 AC: 240 AN: 59674

GnomAD4 genome AF: 0.00317 AC: 483 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00307 AC XY: 229 AN XY: 74476

African (AFR) AF: 0.000722 AC: 30 AN: 41560

American (AMR) AF: 0.00137 AC: 21 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00734 AC: 78 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00382 Hom.: 2

Bravo AF: 0.00267

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00593 AC: 51

ExAC AF: 0.00306 AC: 371

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Joubert syndrome (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.26	N
PhyloP100		3.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.12	B
Vest4		0.43
MVP		0.76
MPC		0.12
ClinPred		0.012	T
GERP RS		5.9
Varity_R		0.085
gMVP		0.25
Mutation Taster		=100/0	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: rs138155747; hg19: chr16-53692694; COSMIC: COSV99030258;