Genetic Variant RUFY1:p.Asp98Tyr (chr5-179550861-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_025158.5(RUFY1):c.292G>T(p.Asp98Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000965 in 1,035,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D98N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 9.7e-7 ( 0 hom. )

Consequence

RUFY1
NM_025158.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.98

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUFY1	NM_025158.5 link	c.292G>T	p.Asp98Tyr	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.292G>T	p.Asp98Tyr	missense_variant	Exon 1 of 18	1	NM_025158.5	ENSP00000325594.4	Q96T51-1
RUFY1	ENST00000393448.6 link	n.25G>T		non_coding_transcript_exon_variant	Exon 1 of 16	1		ENSP00000377094.2	J3KPP6
RUFY1	ENST00000502984.5 link	c.22G>T	p.Asp8Tyr	missense_variant	Exon 1 of 6	3		ENSP00000425533.1	H0Y9Y8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.65e-7

AC:

AN:

1035836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

491154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20672

American (AMR)

AF:

0.00

AC:

AN:

6480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11712

East Asian (EAS)

AF:

0.00

AC:

AN:

21004

South Asian (SAS)

AF:

0.00

AC:

AN:

20242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2644

European-Non Finnish (NFE)

AF:

0.00000112

AC:

AN:

894168

Other (OTH)

AF:

0.00

AC:

AN:

39732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.064

Eigen

Benign

0.058

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.86

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.1

PhyloP100

4.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.3

REVEL

Benign

0.16

Sift

Uncertain

0.0070

Sift4G

Benign

0.13

Polyphen

0.65

Vest4

0.42

MutPred

0.29

Gain of catalytic residue at D98 (P = 0.0019);

MVP

0.63

MPC

0.28

ClinPred

0.58

GERP RS

4.0

PromoterAI

-0.045

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.26

gMVP

0.43

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.62

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.62

Position offset: -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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over