16-53649119-C-G

Variant names:

• chr16-53649119-C-G
• rs201380599
• NM_015272.5:c.2153-4G>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.2153-4G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00239 in 1,613,216 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: RPGRIP1L NM_015272.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001184
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.0260
• Publications: 1 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 Submitted by: 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 (BayesDel_noAF=-0.78).
• BP6: Variant 16-53649119-C-G is Benign according to our data. Variant chr16-53649119-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95689.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00152 (231/152178) while in subpopulation NFE AF = 0.00262 (178/68012). AF 95% confidence interval is 0.0023. There are 0 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.2153-4G>C		splice_region intron	N/A	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.2153-4G>C		splice_region intron	N/A	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.2153-4G>C		splice_region intron	N/A	NP_001295263.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.2153-4G>C		splice_region intron	N/A	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2153-4G>C		splice_region intron	N/A	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.2153-4G>C		splice_region intron	N/A	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00152 AC: 381 AN: 251314 AF XY: 0.00150

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00248 AC: 3618 AN: 1461038 Hom.: 8 Cov.: 30 AF XY: 0.00245 AC XY: 1779 AN XY: 726920

African (AFR) AF: 0.000628 AC: 21 AN: 33462

American (AMR) AF: 0.000760 AC: 34 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00291 AC: 76 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86234

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00297 AC: 3301 AN: 1111312

Other (OTH) AF: 0.00157 AC: 95 AN: 60358

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74382

African (AFR) AF: 0.000626 AC: 26 AN: 41520

American (AMR) AF: 0.000524 AC: 8 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00246 Hom.: 0

Bravo AF: 0.00154

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00267

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Joubert syndrome 7 (1)
-	1	-	Meckel syndrome, type 5 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	1	-	Nephronophthisis 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.39
PhyloP100		0.026
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0040
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: rs201380599; hg19: chr16-53683031;