2-218073269-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198483.4(RUFY4):ā€‹c.413T>Cā€‹(p.Leu138Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000187 in 1,552,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

RUFY4
NM_198483.4 missense

Scores

4
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.27
Variant links:
Genes affected
RUFY4 (HGNC:24804): (RUN and FYVE domain containing 4) Enables phosphatidylinositol-3-phosphate binding activity. Involved in autophagosome assembly; cellular response to interleukin-4; and positive regulation of macroautophagy. Located in autophagosome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RUFY4NM_198483.4 linkuse as main transcriptc.413T>C p.Leu138Pro missense_variant 7/13 ENST00000697321.1 NP_940885.2 Q6ZNE9-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RUFY4ENST00000697321.1 linkuse as main transcriptc.413T>C p.Leu138Pro missense_variant 7/13 NM_198483.4 ENSP00000513250.1 Q6ZNE9-2
RUFY4ENST00000374155.7 linkuse as main transcriptc.413T>C p.Leu138Pro missense_variant 6/122 ENSP00000363270.3 C9J235

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000772
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000189
AC:
3
AN:
158442
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
83672
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000179
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000162
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
22
AN:
1400264
Hom.:
0
Cov.:
33
AF XY:
0.0000159
AC XY:
11
AN XY:
690718
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000280
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000557
Gnomad4 SAS exome
AF:
0.0000505
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000834
Gnomad4 OTH exome
AF:
0.0000861
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152292
Hom.:
0
Cov.:
32
AF XY:
0.0000671
AC XY:
5
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000773
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000151

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 submitterclinical testingAmbry GeneticsNov 11, 2024The c.413T>C (p.L138P) alteration is located in exon 7 (coding exon 5) of the RUFY4 gene. This alteration results from a T to C substitution at nucleotide position 413, causing the leucine (L) at amino acid position 138 to be replaced by a proline (P). 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
Pathogenic
0.82
BayesDel_addAF
Benign
-0.089
T
BayesDel_noAF
Benign
-0.090
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T;T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.73
T;T
M_CAP
Benign
0.030
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.6
.;M
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0040
D;D
Vest4
0.74
MutPred
0.65
Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP
0.45
MPC
0.26
ClinPred
0.85
D
GERP RS
4.6
Varity_R
0.84
gMVP
0.89

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.

Other links and lift over

dbSNP: rs1037140552; hg19: chr2-218937992; API