Genetic Variant RIC1:p.Val552Val (chr9-5754894-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_020829.4(RIC1):c.1656C>A(p.Val552Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,571,104 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 9 hom. )

Consequence

RIC1
NM_020829.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.650

Publications

1 publications found

Variant links:

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 links:

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]

ERMP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.098).

BP6

Variant 9-5754894-C-A is Benign according to our data. Variant chr9-5754894-C-A is described in ClinVar as Benign. ClinVar VariationId is 769749.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.65 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000617 (875/1419030) while in subpopulation AMR AF = 0.0185 (818/44312). AF 95% confidence interval is 0.0174. There are 9 homozygotes in GnomAdExome4. There are 352 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIC1	NM_020829.4	MANE Select	c.1656C>A	p.Val552Val	synonymous	Exon 15 of 26	NP_065880.2	Q4ADV7-1
RIC1	NM_001206557.2		c.1545C>A	p.Val515Val	synonymous	Exon 14 of 25	NP_001193486.1	Q4ADV7-3
RIC1	NM_001135920.4		c.1656C>A	p.Val552Val	synonymous	Exon 15 of 22	NP_001129392.2	Q4ADV7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RIC1	ENST00000414202.7	TSL:5 MANE Select	c.1656C>A	p.Val552Val	synonymous	Exon 15 of 26	ENSP00000416696.2	Q4ADV7-1
RIC1	ENST00000545641.5	TSL:1	c.1329C>A	p.Val443Val	synonymous	Exon 13 of 24	ENSP00000439488.1	H0YFN7
RIC1	ENST00000251879.10	TSL:1	c.1656C>A	p.Val552Val	synonymous	Exon 15 of 22	ENSP00000251879.6	Q4ADV7-2

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0101

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:

0.000959

GnomAD2 exomes

AF:

0.00277

AC:

694

AN:

250166

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.000617

AC:

875

AN:

1419030

Hom.:

Cov.:

AF XY:

0.000500

AC XY:

352

AN XY:

703628

show subpopulations

African (AFR)

AF:

0.000211

AC:

AN:

33126

American (AMR)

AF:

0.0185

AC:

818

AN:

44312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25130

East Asian (EAS)

AF:

0.00

AC:

AN:

39218

South Asian (SAS)

AF:

0.00

AC:

AN:

77714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5372

European-Non Finnish (NFE)

AF:

0.00000738

AC:

AN:

1084476

Other (OTH)

AF:

0.000722

AC:

AN:

58160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152074

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41460

American (AMR)

AF:

0.0103

AC:

158

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.000949

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000466

Hom.:

Bravo

AF:

0.00181

Asia WGS

AF:

0.00116

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

5.0

(source)

DANN

Benign

0.77

PhyloP100

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over