Genetic Variant RUFY1:p.Leu16Pro (chr5-179550616-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_025158.5(RUFY1):c.47T>C(p.Leu16Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000795 in 1,258,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. L16R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

RUFY1
NM_025158.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12424636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUFY1	NM_025158.5 link	c.47T>C	p.Leu16Pro	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>C	p.Leu16Pro	missense_variant	Exon 1 of 18	1	NM_025158.5	ENSP00000325594.4	Q96T51-1
RUFY1	ENST00000393448.6 link	n.-221T>C		upstream_gene_variant		1		ENSP00000377094.2	J3KPP6
RUFY1	ENST00000502984.5 link	c.-224T>C		upstream_gene_variant		3		ENSP00000425533.1	H0Y9Y8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.95e-7

AC:

AN:

1258532

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

620428

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25332

American (AMR)

AF:

0.00

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:

0.00

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:

0.00

AC:

AN:

50372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

0.046

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.36

CADD

Benign

6.1

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.021

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.040

M_CAP

Benign

0.0055

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.34

PhyloP100

-1.3

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.22

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.22

Polyphen

0.94

Vest4

0.18

MutPred

0.21

Loss of sheet (P = 0.0228);

MVP

0.40

MPC

0.35

ClinPred

0.59

GERP RS

0.20

PromoterAI

0.051

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.093

gMVP

0.18

Mutation Taster

=97/3

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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chr5-179550616-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over