chr12-49642269-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001031698.3(PRPF40B):​c.1919G>A​(p.Arg640Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PRPF40B
NM_001031698.3 missense

Scores

4
5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.31
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 -4 ACMG points.

BS2
High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PRPF40BNM_001031698.3 linkuse as main transcriptc.1919G>A p.Arg640Gln missense_variant 20/26 ENST00000548825.7 NP_001026868.2
FMNL3NM_175736.5 linkuse as main transcriptc.*3546C>T 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.1919G>A p.Arg640Gln missense_variant 20/265 NM_001031698.3 ENSP00000448073 P3
FMNL3ENST00000335154.10 linkuse as main transcriptc.*3546C>T 3_prime_UTR_variant 26/261 NM_175736.5 ENSP00000335655 Q8IVF7-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.0000160
AC:
4
AN:
249736
Hom.:
0
AF XY:
0.00000740
AC XY:
1
AN XY:
135104
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000287
AC:
42
AN:
1461854
Hom.:
0
Cov.:
31
AF XY:
0.0000289
AC XY:
21
AN XY:
727220
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:
0.0000464
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000189
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 GeneticsMay 09, 2023The c.1853G>A (p.R618Q) alteration is located in exon 19 (coding exon 19) of the PRPF40B gene. This alteration results from a G to A substitution at nucleotide position 1853, causing the arginine (R) at amino acid position 618 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
0.28
BayesDel_addAF
Benign
0.0039
T
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.10
T;.;T
Eigen
Pathogenic
0.74
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Uncertain
0.63
D;D;D
MetaSVM
Benign
-0.91
T
MutationAssessor
Uncertain
2.3
.;.;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.3
.;D;D
REVEL
Benign
0.27
Sift
Benign
0.051
.;T;T
Sift4G
Benign
0.076
T;T;T
Polyphen
0.99, 0.98
.;D;D
Vest4
0.73
MutPred
0.38
.;.;Gain of ubiquitination at K620 (P = 0.0303);
MVP
0.46
MPC
0.83
ClinPred
0.87
D
GERP RS
4.6
Varity_R
0.34
gMVP
0.66

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: rs753466497; hg19: chr12-50036052; API