12-123533348-G-C

Position:

• chr12-123533348-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000376874.9(RILPL1):​c.135C>G​(p.His45Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,260 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RILPL1 ENST00000376874.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

RILPL1 (HGNC:26814): (Rab interacting lysosomal protein like 1) Predicted to enable protein dimerization activity. Predicted to be involved in several processes, including cilium assembly; epithelial cell morphogenesis; and protein transport from ciliary membrane to plasma membrane. Located in cytosol; nucleoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RILPL1	NM_178314.5	c.135C>G	p.His45Gln	missense_variant	1/7	ENST00000376874.9	NP_847884.2
RILPL1	NM_001319243.2	c.135C>G	p.His45Gln	missense_variant	1/8		NP_001306172.1
RILPL1	XM_047428787.1	c.135C>G	p.His45Gln	missense_variant	1/7		XP_047284743.1
RILPL1	XM_047428788.1	c.135C>G	p.His45Gln	missense_variant	1/3		XP_047284744.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RILPL1	ENST00000376874.9	c.135C>G	p.His45Gln	missense_variant	1/7	1	NM_178314.5	ENSP00000366070.4
RILPL1	ENST00000636882.1	c.135C>G	p.His45Gln	missense_variant	1/8	5		ENSP00000490668.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427260 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707462

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: 0.00

Gnomad4 NFE exome AF: 9.12e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.135C>G (p.H45Q) alteration is located in exon 1 (coding exon 1) of the RILPL1 gene. This alteration results from a C to G substitution at nucleotide position 135, causing the histidine (H) at amino acid position 45 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.8	D;.
REVEL	Benign	0.14
Sift	Benign	0.084	T;.
Sift4G	Benign	0.091	T;.
Polyphen		0.62	P;.
Vest4		0.39
MutPred		0.77		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.57
MPC		1.9
ClinPred		0.89	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.82

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: rs1885513317; hg19: chr12-124017895;