16-53658781-C-G

Variant names:

• chr16-53658781-C-G
• rs61743997
• NM_015272.5:c.1341G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_015272.5(RPGRIP1L):​c.1341G>C​(p.Leu447Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,439,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. L447S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: RPGRIP1L NM_015272.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-53658782-A-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.041024745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGRIP1L	NM_015272.5	c.1341G>C	p.Leu447Phe	missense_variant	Exon 11 of 27	ENST00000647211.2	NP_056087.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.1341G>C	p.Leu447Phe	missense_variant	Exon 11 of 27		NM_015272.5	ENSP00000493946.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000856 AC: 2 AN: 233538 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 125896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000194

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000556 AC: 8 AN: 1439688 Hom.: 0 Cov.: 28 AF XY: 0.00000838 AC XY: 6 AN XY: 715774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.00000547

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.23
DEOGEN2	Benign	0.0030	.;.;T;.;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.58	T;.;T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.041	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.8	N;N;.;N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N;.;.;N;N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;.;.;T;T;T
Sift4G	Benign	1.0	T;.;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.
Vest4		0.24
MutPred		0.20		Gain of methylation at K446 (P = 0.0275);Gain of methylation at K446 (P = 0.0275);Gain of methylation at K446 (P = 0.0275);Gain of methylation at K446 (P = 0.0275);Gain of methylation at K446 (P = 0.0275);Gain of methylation at K446 (P = 0.0275);
MVP		0.70
MPC		0.078
ClinPred		0.019	T
GERP RS		3.7
Varity_R		0.049
gMVP		0.075

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

Publications

LitVar

Other links and lift over

dbSNP: rs61743997; hg19: chr16-53692693;