NM_020829.4:c.1808C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A603G) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020829.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIC1	NM_020829.4	MANE Select	c.1808C>T	p.Ala603Val	missense	Exon 16 of 26	NP_065880.2	Q4ADV7-1
	RIC1	NM_001206557.2		c.1697C>T	p.Ala566Val	missense	Exon 15 of 25	NP_001193486.1	Q4ADV7-3
	RIC1	NM_001135920.4		c.1808C>T	p.Ala603Val	missense	Exon 16 of 22	NP_001129392.2	Q4ADV7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIC1	ENST00000414202.7	TSL:5 MANE Select	c.1808C>T	p.Ala603Val	missense	Exon 16 of 26	ENSP00000416696.2	Q4ADV7-1
	RIC1	ENST00000545641.5	TSL:1	c.1481C>T	p.Ala494Val	missense	Exon 14 of 24	ENSP00000439488.1	H0YFN7
	RIC1	ENST00000251879.10	TSL:1	c.1808C>T	p.Ala603Val	missense	Exon 16 of 22	ENSP00000251879.6	Q4ADV7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240668 AF XY: 0.00

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32502

American (AMR) AF: 0.00 AC: 0 AN: 42610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25344

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38558

South Asian (SAS) AF: 0.00 AC: 0 AN: 80134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089722

Other (OTH) AF: 0.00 AC: 0 AN: 58462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Uncertain	0.013	D
Sift4G	Benign	0.072	T
Polyphen		0.019	B
Vest4		0.65
MutPred		0.50		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
Mutation Taster		=41/59	disease causing

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

Other links and lift over

dbSNP: rs200919699; hg19: chr9-5756327;