chr12-49636719-T-C

Variant summary

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

The NM_001031698.3(PRPF40B):ā€‹c.1430T>Cā€‹(p.Met477Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

PRPF40B
NM_001031698.3 missense

Scores

9
6
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99
Variant links:
Genes affected
PRPF40B (HGNC:25031): (pre-mRNA processing factor 40 homolog B) This gene encodes a WW-domain containing protein similar to yeast splicing factor PRP40. This protein has been shown to interact with Huntingtin and methyl CpG binding protein 2 (MeCP2). Alternative splicing results in different transcript variants. [provided by RefSeq, Aug 2014]
FMNL3 (HGNC:23698): (formin like 3) The protein encoded by this gene contains a formin homology 2 domain and has high sequence identity to the mouse Wbp3 protein. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

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, 0.804

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRPF40BNM_001031698.3 linkuse as main transcriptc.1430T>C p.Met477Thr missense_variant 16/26 ENST00000548825.7 NP_001026868.2
FMNL3NM_175736.5 linkuse as main transcriptc.*9096A>G 3_prime_UTR_variant 26/26 ENST00000335154.10 NP_783863.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PRPF40BENST00000548825.7 linkuse as main transcriptc.1430T>C p.Met477Thr missense_variant 16/265 NM_001031698.3 ENSP00000448073 P3
PRPF40BENST00000380281.6 linkuse as main transcriptc.1430T>C p.Met477Thr missense_variant 16/261 ENSP00000369634 A2
PRPF40BENST00000261897.5 linkuse as main transcriptc.1346T>C p.Met449Thr missense_variant 15/251 ENSP00000261897 Q6NWY9-2
FMNL3ENST00000335154.10 linkuse as main transcriptc.*9096A>G 3_prime_UTR_variant 26/261 NM_175736.5 ENSP00000335655 Q8IVF7-3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461794
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727190
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

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 GeneticsApr 01, 2024The c.1364T>C (p.M455T) alteration is located in exon 15 (coding exon 15) of the PRPF40B gene. This alteration results from a T to C substitution at nucleotide position 1364, causing the methionine (M) at amino acid position 455 to be replaced by a threonine (T). 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
0.99
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.16
T;.;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.80
D;D;D
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.7
.;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.4
.;D;D
REVEL
Uncertain
0.47
Sift
Pathogenic
0.0
.;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
0.99, 0.99
.;D;D
Vest4
0.92
MutPred
0.38
.;.;Loss of stability (P = 0.0021);
MVP
0.69
MPC
0.84
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.90
gMVP
0.84

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: rs754436465; hg19: chr12-50030502; API