rs559978421

Variant names:

• chr16-53687846-CA-C
• rs559978421
• NM_015272.5:c.632+16delT

Your query was ambiguous. Multiple possible variants found:

• chr16-53687846-CA-C
• chr16-53687846-CA-CAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015272.5(RPGRIP1L):​c.632+16delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,482,226 control chromosomes in the GnomAD database, including 50 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (47 hom.)
• Consequence: RPGRIP1L NM_015272.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.350
• 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, 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 -16 ACMG points.

• BP6: Variant 16-53687846-CA-C is Benign according to our data. Variant chr16-53687846-CA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00503 (763/151818) while in subpopulation NFE AF = 0.00869 (590/67862). AF 95% confidence interval is 0.00811. There are 3 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.632+16delT		intron	N/A	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.632+16delT		intron	N/A	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.632+16delT		intron	N/A	NP_001295263.1	A0A087WX34

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.632+16delT		intron	N/A	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.632+16delT		intron	N/A	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.632+16delT		intron	N/A	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 763 AN: 151702 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00181

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00869

Gnomad OTH AF: 0.00385

GnomAD2 exomes AF: 0.00445 AC: 1112 AN: 249882 AF XY: 0.00453

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00789

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00731 AC: 9729 AN: 1330408 Hom.: 47 Cov.: 21 AF XY: 0.00702 AC XY: 4703 AN XY: 669700

African (AFR) AF: 0.00101 AC: 31 AN: 30816

American (AMR) AF: 0.00245 AC: 109 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.00428 AC: 108 AN: 25230

East Asian (EAS) AF: 0.00 AC: 0 AN: 38846

South Asian (SAS) AF: 0.00 AC: 0 AN: 83170

European-Finnish (FIN) AF: 0.00164 AC: 87 AN: 53210

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5436

European-Non Finnish (NFE) AF: 0.00918 AC: 9118 AN: 993248

Other (OTH) AF: 0.00491 AC: 275 AN: 55992

GnomAD4 genome AF: 0.00503 AC: 763 AN: 151818 Hom.: 3 Cov.: 32 AF XY: 0.00466 AC XY: 346 AN XY: 74188

African (AFR) AF: 0.00179 AC: 74 AN: 41422

American (AMR) AF: 0.00341 AC: 52 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

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

European-Finnish (FIN) AF: 0.00181 AC: 19 AN: 10502

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

European-Non Finnish (NFE) AF: 0.00869 AC: 590 AN: 67862

Other (OTH) AF: 0.00381 AC: 8 AN: 2100

Alfa AF: 0.00556 Hom.: 0

Bravo AF: 0.00516

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs559978421; hg19: chr16-53721758;