rs190689604

Variant names:

• chr16-53638442-T-C
• rs190689604
• NM_015272.5:c.2959-31A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000647211.2(RPGRIP1L):​c.2959-31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,164,108 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: RPGRIP1L ENST00000647211.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.07
• Publications: 0 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-53638442-T-C is Benign according to our data. Variant chr16-53638442-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 260602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00142 (216/152126) while in subpopulation AMR AF = 0.00281 (43/15278). AF 95% confidence interval is 0.00215. There are 0 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647211.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.2959-31A>G		intron	N/A	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.2959-588A>G		intron	N/A	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.2959-31A>G		intron	N/A	NP_001295263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.2959-31A>G		intron	N/A	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2959-588A>G		intron	N/A	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.2959-31A>G		intron	N/A	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00118 AC: 288 AN: 243992 AF XY: 0.00116

Gnomad AFR exome AF: 0.000769

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.00156 AC: 1576 AN: 1011982 Hom.: 5 Cov.: 14 AF XY: 0.00155 AC XY: 808 AN XY: 522918

African (AFR) AF: 0.000363 AC: 9 AN: 24772

American (AMR) AF: 0.00162 AC: 71 AN: 43764

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23282

East Asian (EAS) AF: 0.00 AC: 0 AN: 37422

South Asian (SAS) AF: 0.00 AC: 0 AN: 76744

European-Finnish (FIN) AF: 0.000192 AC: 10 AN: 52188

Middle Eastern (MID) AF: 0.000204 AC: 1 AN: 4906

European-Non Finnish (NFE) AF: 0.00201 AC: 1410 AN: 703158

Other (OTH) AF: 0.00164 AC: 75 AN: 45746

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74368

African (AFR) AF: 0.000433 AC: 18 AN: 41558

American (AMR) AF: 0.00281 AC: 43 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 67896

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00137

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		1.1
BranchPoint Hunter		2.0
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: rs190689604; hg19: chr16-53672354;