rs368039428

Variant names:

• chr9-5720734-G-A
• rs368039428
• NM_020829.4:c.704G>A

Variant summary

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

The NM_020829.4(RIC1):​c.704G>A​(p.Ser235Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RIC1 NM_020829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• 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]

RIC1 Gene-Disease associations (from GenCC):

• Catifa syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

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=0.12382227).

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.704G>A	p.Ser235Asn	missense	Exon 6 of 26	NP_065880.2	Q4ADV7-1
	RIC1	NM_001206557.2		c.704G>A	p.Ser235Asn	missense	Exon 6 of 25	NP_001193486.1	Q4ADV7-3
	RIC1	NM_001135920.4		c.704G>A	p.Ser235Asn	missense	Exon 6 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.704G>A	p.Ser235Asn	missense	Exon 6 of 26	ENSP00000416696.2	Q4ADV7-1
	RIC1	ENST00000545641.5	TSL:1	c.488G>A	p.Ser163Asn	missense	Exon 5 of 24	ENSP00000439488.1	H0YFN7
	RIC1	ENST00000251879.10	TSL:1	c.704G>A	p.Ser235Asn	missense	Exon 6 of 22	ENSP00000251879.6	Q4ADV7-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243272 AF XY: 0.00000760

Gnomad AFR exome AF: 0.0000627

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.87e-7 AC: 1 AN: 1455752 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724162

African (AFR) AF: 0.0000302 AC: 1 AN: 33104

American (AMR) AF: 0.00 AC: 0 AN: 43256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39474

South Asian (SAS) AF: 0.00 AC: 0 AN: 84876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109816

Other (OTH) AF: 0.00 AC: 0 AN: 60128

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.34	N
PhyloP100		3.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.079
Sift	Benign	0.46	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.25
MVP		0.043
ClinPred		0.22	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.16
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368039428; hg19: chr9-5720734; COSMIC: COSV107247767; COSMIC: COSV107247767;