chr12-49643244-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001031698.3(PRPF40B):ā€‹c.2227G>Cā€‹(p.Glu743Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

PRPF40B
NM_001031698.3 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46
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 Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10423428).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRPF40BNM_001031698.3 linkuse as main transcriptc.2227G>C p.Glu743Gln missense_variant 23/26 ENST00000548825.7 NP_001026868.2
FMNL3NM_175736.5 linkuse as main transcriptc.*2571C>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.2227G>C p.Glu743Gln missense_variant 23/265 NM_001031698.3 ENSP00000448073 P3
FMNL3ENST00000335154.10 linkuse as main transcriptc.*2571C>G 3_prime_UTR_variant 26/261 NM_175736.5 ENSP00000335655 Q8IVF7-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
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:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249258
Hom.:
0
AF XY:
0.00000741
AC XY:
1
AN XY:
134894
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461822
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152290
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000962
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
Bravo
AF:
0.0000227
ExAC
AF:
0.0000165
AC:
2

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 GeneticsMar 31, 2024The c.2164G>C (p.E722Q) alteration is located in exon 22 (coding exon 22) of the PRPF40B gene. This alteration results from a G to C substitution at nucleotide position 2164, causing the glutamic acid (E) at amino acid position 722 to be replaced by a glutamine (Q). 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
Benign
0.10
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.46
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
T;.;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.0063
T
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.81
.;.;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.99
.;N;N
REVEL
Benign
0.025
Sift
Uncertain
0.018
.;D;D
Sift4G
Benign
0.55
T;T;T
Polyphen
0.94, 0.90
.;P;P
Vest4
0.34
MutPred
0.25
.;.;Gain of catalytic residue at L723 (P = 2e-04);
MVP
0.25
MPC
0.51
ClinPred
0.26
T
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.44

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: rs566253760; hg19: chr12-50037027; API