9-5756327-C-T

Variant names:

• chr9-5756327-C-T
• rs200919699
• NM_020829.4:c.1808C>T

Variant summary

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

The NM_020829.4(RIC1):​c.1808C>T​(p.Ala603Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RIC1 NM_020829.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75

Genes affected

RIC1 (HGNC:17686): (RIC1 homolog, RAB6A GEF complex partner 1) Enables guanyl-nucleotide exchange factor activity and small GTPase binding activity. Involved in several processes, including positive regulation of GTPase activity; regulation of extracellular matrix constituent secretion; and retrograde transport, endosome to Golgi. Located in cytosol and membrane. Part of Ric1-Rgp1 guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ERMP1 (HGNC:23703): (endoplasmic reticulum metallopeptidase 1) Predicted to enable metal ion binding activity and metalloexopeptidase activity. Involved in cellular response to oxidative stress. Acts upstream of or within endoplasmic reticulum unfolded protein response. Located in 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 rank	MANE	Protein	UniProt
RIC1	NM_020829.4	c.1808C>T	p.Ala603Val	missense_variant	Exon 16 of 26	ENST00000414202.7	NP_065880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIC1	ENST00000414202.7	c.1808C>T	p.Ala603Val	missense_variant	Exon 16 of 26	5	NM_020829.4	ENSP00000416696.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240668 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000575

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424820 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 707344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;.;T
Eigen	Benign	0.042
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D;.;D
REVEL	Benign	0.18
Sift	Uncertain	0.013	D;.;D
Sift4G	Benign	0.072	T;T;T
Polyphen		0.019	.;.;B
Vest4		0.65
MutPred		0.50		Loss of catalytic residue at A603 (P = 0.0636);.;Loss of catalytic residue at A603 (P = 0.0636);
MVP		0.093
ClinPred		0.65	D
GERP RS		5.0
Varity_R		0.32
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200919699; hg19: chr9-5756327;