rs561414163

Variant names:

• chr16-53622256-T-C
• rs561414163
• NM_015272.5:c.3395A>G

Variant summary

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

The NM_015272.5(RPGRIP1L):​c.3395A>G​(p.Gln1132Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 657,008 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q1132Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (5 hom., cov: 29)
  • Exomes 𝑓: 0.0052 (86 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.214
• 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):

• 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: Computational evidence support a benign effect (MetaRNN=0.0036060512).
• BP6: Variant 16-53622256-T-C is Benign according to our data. Variant chr16-53622256-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00153 (226/148064) while in subpopulation SAS AF = 0.0474 (220/4642). AF 95% confidence interval is 0.0423. There are 5 homozygotes in GnomAd4. There are 173 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.3395A>G	p.Gln1132Arg	missense	Exon 23 of 27	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.3293A>G	p.Gln1098Arg	missense	Exon 22 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.3295-3048A>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.3395A>G	p.Gln1132Arg	missense	Exon 23 of 27	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3293A>G	p.Gln1098Arg	missense	Exon 22 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3295-3048A>G		intron	N/A	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 225 AN: 147946 Hom.: 5 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000612

Gnomad SAS AF: 0.0471

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.000982

GnomAD2 exomes AF: 0.00769 AC: 821 AN: 106826 AF XY: 0.0108

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.0000980

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000254

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00522 AC: 2659 AN: 508944 Hom.: 86 Cov.: 0 AF XY: 0.00775 AC XY: 2125 AN XY: 274366

African (AFR) AF: 0.000144 AC: 2 AN: 13928

American (AMR) AF: 0.0000645 AC: 2 AN: 31030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18744

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30138

South Asian (SAS) AF: 0.0456 AC: 2591 AN: 56876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31834

Middle Eastern (MID) AF: 0.00131 AC: 3 AN: 2284

European-Non Finnish (NFE) AF: 0.0000406 AC: 12 AN: 295600

Other (OTH) AF: 0.00168 AC: 48 AN: 28510

GnomAD4 genome AF: 0.00153 AC: 226 AN: 148064 Hom.: 5 Cov.: 29 AF XY: 0.00240 AC XY: 173 AN XY: 72222

African (AFR) AF: 0.00 AC: 0 AN: 40044

American (AMR) AF: 0.00 AC: 0 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3438

East Asian (EAS) AF: 0.000613 AC: 3 AN: 4892

South Asian (SAS) AF: 0.0474 AC: 220 AN: 4642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 66998

Other (OTH) AF: 0.000971 AC: 2 AN: 2060

Alfa AF: 0.000471 Hom.: 0

ExAC AF: 0.0227 AC: 323

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Joubert syndrome 7 (1)
-	-	1	Kidney disorder (1)
-	-	1	Meckel syndrome, type 5 (1)
-	-	1	Meckel syndrome, type 5;C1969053:Joubert syndrome 7;C5436841:COACH syndrome 3 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)
-	-	1	Nephronophthisis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.3
DANN	Benign	0.13
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.21
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.012
Sift	Benign	0.52	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.16
MutPred		0.27		Loss of sheet (P = 0.0315)
MPC		0.077
ClinPred		0.014	T
GERP RS		0.16
Varity_R		0.079
gMVP		0.097
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs561414163; hg19: chr16-53656168;