rs144313291

Variant names:

• chr16-53641066-T-C
• rs144313291
• NM_015272.5:c.2925A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_015272.5(RPGRIP1L):​c.2925A>G​(p.Val975Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00632 in 1,613,756 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (51 hom.)
• Consequence: RPGRIP1L NM_015272.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -1.35
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 16-53641066-T-C is Benign according to our data. Variant chr16-53641066-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95691.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00502 (764/152318) while in subpopulation NFE AF = 0.00667 (454/68020). AF 95% confidence interval is 0.00617. There are 7 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.2925A>G	p.Val975Val	synonymous	Exon 19 of 27	NP_056087.2	Q68CZ1-1
	RPGRIP1L	NM_001330538.2		c.2925A>G	p.Val975Val	synonymous	Exon 19 of 26	NP_001317467.1	H3BV03
	RPGRIP1L	NM_001308334.3		c.2925A>G	p.Val975Val	synonymous	Exon 19 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.2925A>G	p.Val975Val	synonymous	Exon 19 of 27	ENSP00000493946.1	Q68CZ1-1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.2925A>G	p.Val975Val	synonymous	Exon 19 of 26	ENSP00000457889.1	H3BV03
	RPGRIP1L	ENST00000621565.5	TSL:1	c.2925A>G	p.Val975Val	synonymous	Exon 19 of 26	ENSP00000480698.1	A0A087WX34

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 763 AN: 152200 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00667

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00544 AC: 1365 AN: 250776 AF XY: 0.00539

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.00729

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00646 AC: 9443 AN: 1461438 Hom.: 51 Cov.: 30 AF XY: 0.00636 AC XY: 4627 AN XY: 727034

African (AFR) AF: 0.000538 AC: 18 AN: 33474

American (AMR) AF: 0.000671 AC: 30 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39666

South Asian (SAS) AF: 0.00128 AC: 110 AN: 86248

European-Finnish (FIN) AF: 0.0194 AC: 1035 AN: 53378

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.00715 AC: 7944 AN: 1111684

Other (OTH) AF: 0.00479 AC: 289 AN: 60382

GnomAD4 genome AF: 0.00502 AC: 764 AN: 152318 Hom.: 7 Cov.: 32 AF XY: 0.00501 AC XY: 373 AN XY: 74498

African (AFR) AF: 0.00113 AC: 47 AN: 41572

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.0215 AC: 228 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00667 AC: 454 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00450 Hom.: 1

Bravo AF: 0.00380

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00581

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Joubert syndrome (1)
-	-	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 provided (1)
-	-	1	RPGRIP1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.4
DANN	Benign	0.68
PhyloP100		-1.4
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: rs144313291; hg19: chr16-53674978;