Genetic Variant FYTTD1:p.Ala21Val (chr3-197750033-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032288.7(FYTTD1):c.62C>T(p.Ala21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,430,154 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. A21P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

FYTTD1
NM_032288.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.550

Publications

0 publications found

Variant links:

Genes affected

FYTTD1 (HGNC:25407): (forty-two-three domain containing 1) Enables mRNA binding activity. Involved in mRNA export from nucleus. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

FYTTD1 links:

RUBCN (HGNC:28991): (rubicon autophagy regulator) The protein encoded by this gene is a negative regulator of autophagy and endocytic trafficking and controls endosome maturation. This protein contains two conserved domains, an N-terminal RUN domain and a C-terminal DUF4206 domain. The RUN domain is involved in Ras-like GTPase signaling, and the DUF4206 domain contains a diacylglycerol (DAG) binding-like motif. Mutation in this gene results in deletion of the DAG binding-like motif and causes a recessive ataxia. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

RUBCN Gene-Disease associations (from GenCC):

autosomal recessive spinocerebellar ataxia 15
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, Orphanet

RUBCN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032288.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FYTTD1	NM_032288.7	MANE Select	c.62C>T	p.Ala21Val	missense	Exon 1 of 9	NP_115664.2
FYTTD1	NM_001011537.3		c.-141+383C>T		intron	N/A	NP_001011537.2	Q96QD9-2
RUBCN	NM_001145642.5		c.-880G>A		upstream_gene	N/A	NP_001139114.1	Q92622-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FYTTD1	ENST00000241502.9	TSL:1 MANE Select	c.62C>T	p.Ala21Val	missense	Exon 1 of 9	ENSP00000241502.3	Q96QD9-1
FYTTD1	ENST00000966386.1		c.62C>T	p.Ala21Val	missense	Exon 1 of 10	ENSP00000636445.1
FYTTD1	ENST00000966385.1		c.62C>T	p.Ala21Val	missense	Exon 1 of 9	ENSP00000636444.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1430154

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30384

American (AMR)

AF:

0.00

AC:

AN:

41250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25288

East Asian (EAS)

AF:

0.00

AC:

AN:

35466

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097906

Other (OTH)

AF:

0.00

AC:

AN:

59112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.41

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.55

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.3

REVEL

Benign

0.075

Sift

Benign

0.080

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.044

MutPred

0.46

Gain of methylation at K20 (P = 0.0751)

MVP

0.043

MPC

0.18

ClinPred

0.45

GERP RS

3.5

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.24

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.83

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.83

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over