Genetic Variant RUFY1:p.Leu16Arg (chr5-179550616-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_025158.5(RUFY1):c.47T>G(p.Leu16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,302,388 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0000064 ( 0 hom. )

Consequence

RUFY1
NM_025158.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

Publications

1 publications found

Variant links:

Genes affected

RUFY1 (HGNC:19760): (RUN and FYVE domain containing 1) This gene encodes a protein that contains a RUN domain and a FYVE-type zinc finger domain. The encoded protein binds to phosphatidylinositol-3-phosphate (PI3P) and plays a role in early endosomal trafficking, tethering and fusion through interactions with small GTPases including Rab4, Rab5 and Rab14. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

RUFY1 links:

LOC128966623 (HGNC:):

LOC128966623 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03836891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUFY1	NM_025158.5 link	c.47T>G	p.Leu16Arg	missense_variant	Exon 1 of 18	ENST00000319449.9	NP_079434.3	Q96T51-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RUFY1	ENST00000319449.9 link	c.47T>G	p.Leu16Arg	missense_variant	Exon 1 of 18	1	NM_025158.5	ENSP00000325594.4	Q96T51-1
RUFY1	ENST00000393448.6 link	n.-221T>G		upstream_gene_variant		1		ENSP00000377094.2	J3KPP6
RUFY1	ENST00000502984.5 link	c.-224T>G		upstream_gene_variant		3		ENSP00000425533.1	H0Y9Y8

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

43856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00353

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:

0.00174

GnomAD2 exomes

AF:

0.00

AC:

AN:

82300

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000636

AC:

AN:

1258532

Hom.:

Cov.:

AF XY:

0.00000806

AC XY:

AN XY:

620428

show subpopulations

African (AFR)

AF:

0.0000790

AC:

AN:

25332

American (AMR)

AF:

0.0000804

AC:

AN:

24862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21200

East Asian (EAS)

AF:

0.00

AC:

AN:

25612

South Asian (SAS)

AF:

0.0000151

AC:

AN:

66026

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4176

European-Non Finnish (NFE)

AF:

9.89e-7

AC:

AN:

1010626

Other (OTH)

AF:

0.0000397

AC:

AN:

50372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.588

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000296

AC:

AN:

43856

Hom.:

Cov.:

AF XY:

0.000332

AC XY:

AN XY:

21062

show subpopulations

African (AFR)

AF:

0.000129

AC:

AN:

7742

American (AMR)

AF:

0.00353

AC:

AN:

3114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1108

East Asian (EAS)

AF:

0.00

AC:

AN:

568

South Asian (SAS)

AF:

0.00

AC:

AN:

1018

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

25394

Other (OTH)

AF:

0.00174

AC:

AN:

576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.566

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000230

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.47T>G (p.L16R) alteration is located in exon 1 (coding exon 1) of the RUFY1 gene. This alteration results from a T to G substitution at nucleotide position 47, causing the leucine (L) at amino acid position 16 to be replaced by an arginine (R). 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

0.050

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

4.8

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.021

Eigen

Benign

-0.81

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.25

M_CAP

Benign

0.0071

MetaRNN

Benign

0.038

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.69

PhyloP100

-1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.24

REVEL

Benign

0.087

Sift

Benign

0.84

Sift4G

Benign

0.44

Polyphen

0.94

Vest4

0.14

MutPred

0.23

Gain of loop (P = 0.0435);

MVP

0.42

MPC

0.32

ClinPred

0.24

GERP RS

0.20

PromoterAI

0.018

Neutral

(source)

Varity_R

0.14

gMVP

0.16

Mutation Taster

=100/0

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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5-179550616-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over