16-53686524-C-G

Variant names:

• chr16-53686524-C-G
• rs61747071
• NM_015272.5:c.685G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015272.5(RPGRIP1L):​c.685G>C​(p.Ala229Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A229T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09946963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.685G>C	p.Ala229Pro	missense_variant	Exon 6 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.685G>C	p.Ala229Pro	missense_variant	Exon 6 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461428 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727014

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111722

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0064	.;.;T;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.87	D;.;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.099	T;T;T;T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	2.0	M;M;.;M;.;.;.
PhyloP100		-0.022
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.1	N;.;.;N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.25	T;.;.;T;T;T;T
Sift4G	Benign	0.28	T;.;T;T;T;T;T
Polyphen		0.53	P;P;.;P;.;.;.
Vest4		0.41
MutPred		0.21		Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);Loss of MoRF binding (P = 0.1012);
MVP		0.74
MPC		0.18
ClinPred		0.20	T
GERP RS		2.7
Varity_R		0.12
gMVP		0.65
Mutation Taster		=88/12	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: rs61747071; hg19: chr16-53720436;