rs139974543

Variant names:

• chr16-53619093-G-C
• rs139974543
• NM_015272.5:c.3548C>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.3548C>G​(p.Ala1183Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0114 in 1,613,978 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (3 hom., cov: 32)
  • Exomes 𝑓: 0.012 (120 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.72
• Publications: 18 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=0.0074778795).
• BP6: Variant 16-53619093-G-C is Benign according to our data. Variant chr16-53619093-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95693.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 = 0.00829 (1262/152290) while in subpopulation NFE AF = 0.0138 (941/68028). AF 95% confidence interval is 0.0131. There are 3 homozygotes in GnomAd4. There are 555 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	NM_015272.5	MANE Select	c.3548C>G	p.Ala1183Gly	missense	Exon 24 of 27	NP_056087.2
	RPGRIP1L	NM_001330538.2		c.3446C>G	p.Ala1149Gly	missense	Exon 23 of 26	NP_001317467.1
	RPGRIP1L	NM_001308334.3		c.3410C>G	p.Ala1137Gly	missense	Exon 23 of 26	NP_001295263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGRIP1L	ENST00000647211.2	MANE Select	c.3548C>G	p.Ala1183Gly	missense	Exon 24 of 27	ENSP00000493946.1
	RPGRIP1L	ENST00000563746.5	TSL:1	c.3446C>G	p.Ala1149Gly	missense	Exon 23 of 26	ENSP00000457889.1
	RPGRIP1L	ENST00000621565.5	TSL:1	c.3410C>G	p.Ala1137Gly	missense	Exon 23 of 26	ENSP00000480698.1

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00968 AC: 2434 AN: 251490 AF XY: 0.00984

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00591

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0118 AC: 17208 AN: 1461688 Hom.: 120 Cov.: 31 AF XY: 0.0116 AC XY: 8411 AN XY: 727152

African (AFR) AF: 0.00152 AC: 51 AN: 33478

American (AMR) AF: 0.00398 AC: 178 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 429 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00335 AC: 289 AN: 86256

European-Finnish (FIN) AF: 0.00605 AC: 323 AN: 53420

Middle Eastern (MID) AF: 0.000869 AC: 5 AN: 5754

European-Non Finnish (NFE) AF: 0.0137 AC: 15279 AN: 1111850

Other (OTH) AF: 0.0108 AC: 653 AN: 60386

GnomAD4 genome AF: 0.00829 AC: 1262 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00745 AC XY: 555 AN XY: 74468

African (AFR) AF: 0.00166 AC: 69 AN: 41544

American (AMR) AF: 0.00811 AC: 124 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

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

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4828

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0138 AC: 941 AN: 68028

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.0138 Hom.: 10

Bravo AF: 0.00832

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0153 AC: 132

ExAC AF: 0.0103 AC: 1256

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0130

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	1	Joubert syndrome (1)
-	-	1	Joubert syndrome 7 (1)
-	-	1	Meckel syndrome, type 5 (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	0.26
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.27
Sift	Uncertain	0.029	D
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.38
MPC		0.073
ClinPred		0.035	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.20
Mutation Taster		=99/1	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: rs139974543; hg19: chr16-53653005; COSMIC: COSV50908249;