Variant chr9-5629380-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020829.4(RIC1):c.71A>T(p.His24Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000217 in 1,381,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

RIC1
NM_020829.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22967026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIC1	NM_020829.4 linkuse as main transcript	c.71A>T	p.His24Leu	missense_variant	1/26	ENST00000414202.7
LOC124902114	XR_007061406.1 linkuse as main transcript	n.161+187T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIC1	ENST00000414202.7 linkuse as main transcript	c.71A>T	p.His24Leu	missense_variant	1/26	5	NM_020829.4	P1	Q4ADV7-1
RIC1	ENST00000251879.10 linkuse as main transcript	c.71A>T	p.His24Leu	missense_variant	1/22	1			Q4ADV7-2
	ENST00000661858.1 linkuse as main transcript	n.182+187T>A		intron_variant, non_coding_transcript_variant
RIC1	ENST00000418622.7 linkuse as main transcript	c.71A>T	p.His24Leu	missense_variant	1/25	5			Q4ADV7-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1381436

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

681708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2023

The c.71A>T (p.H24L) alteration is located in exon 1 (coding exon 1) of the RIC1 gene. This alteration results from a A to T substitution at nucleotide position 71, causing the histidine (H) at amino acid position 24 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.053

.;.;T

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.67

T;T;T

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;L;L

MutationTaster

Benign

0.91

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.58

N;.;N

REVEL

Benign

0.19

Sift

Benign

0.090

T;.;T

Sift4G

Benign

0.38

T;T;T

Vest4

0.43

MutPred

0.26

Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);

MVP

0.043

ClinPred

0.37

GERP RS

2.6

Varity_R

0.17

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over