9-5756257-C-T

Variant names:

• chr9-5756257-C-T
• rs544522535
• NM_020829.4:c.1738C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020829.4(RIC1):​c.1738C>T​(p.His580Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000287 in 1,602,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H580L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RIC1 NM_020829.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039023757).

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.1738C>T	p.His580Tyr	missense	Exon 16 of 26	NP_065880.2	Q4ADV7-1
	RIC1	NM_001206557.2		c.1627C>T	p.His543Tyr	missense	Exon 15 of 25	NP_001193486.1	Q4ADV7-3
	RIC1	NM_001135920.4		c.1738C>T	p.His580Tyr	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.1738C>T	p.His580Tyr	missense	Exon 16 of 26	ENSP00000416696.2	Q4ADV7-1
	RIC1	ENST00000545641.5	TSL:1	c.1411C>T	p.His471Tyr	missense	Exon 14 of 24	ENSP00000439488.1	H0YFN7
	RIC1	ENST00000251879.10	TSL:1	c.1738C>T	p.His580Tyr	missense	Exon 16 of 22	ENSP00000251879.6	Q4ADV7-2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000161 AC: 40 AN: 247938 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00116

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: 0.000166

GnomAD4 exome AF: 0.0000269 AC: 39 AN: 1450520 Hom.: 0 Cov.: 30 AF XY: 0.0000208 AC XY: 15 AN XY: 721020

African (AFR) AF: 0.00 AC: 0 AN: 33178

American (AMR) AF: 0.000883 AC: 39 AN: 44146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 84302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105134

Other (OTH) AF: 0.00 AC: 0 AN: 59890

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74428

African (AFR) AF: 0.00 AC: 0 AN: 41532

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions

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	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Sift4G	Benign	1.0	T
Polyphen		0.040	B
Vest4		0.66
MutPred		0.42		Gain of ubiquitination at K583 (P = 0.1586)
MVP		0.043
ClinPred		0.062	T
GERP RS		5.9
Varity_R		0.083
gMVP		0.45
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: rs544522535; hg19: chr9-5756257; COSMIC: COSV52614367;