chr12-49636718-A-G

Position:

chr12-49636718-A-G

Variant summary

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

The NM_001031698.3(PRPF40B):c.1429A>G(p.Met477Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

PRPF40B
NM_001031698.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.30

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]

PRPF40B links:

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]

FMNL3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 76 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF40B	NM_001031698.3 linkuse as main transcript	c.1429A>G	p.Met477Val	missense_variant, splice_region_variant	16/26	ENST00000548825.7	NP_001026868.2
FMNL3	NM_175736.5 linkuse as main transcript	c.*9097T>C		3_prime_UTR_variant	26/26	ENST00000335154.10	NP_783863.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF40B	ENST00000548825.7 linkuse as main transcript	c.1429A>G	p.Met477Val	missense_variant, splice_region_variant	16/26	5	NM_001031698.3	ENSP00000448073	P3
PRPF40B	ENST00000380281.6 linkuse as main transcript	c.1429A>G	p.Met477Val	missense_variant, splice_region_variant	16/26	1		ENSP00000369634	A2
PRPF40B	ENST00000261897.5 linkuse as main transcript	c.1345A>G	p.Met449Val	missense_variant, splice_region_variant	15/25	1		ENSP00000261897		Q6NWY9-2
FMNL3	ENST00000335154.10 linkuse as main transcript	c.*9097T>C		3_prime_UTR_variant	26/26	1	NM_175736.5	ENSP00000335655		Q8IVF7-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251462

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135900

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727198

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:

0.0000187

Gnomad4 NFE exome

AF:

0.0000648

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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 submitter

clinical testing

Ambry Genetics

May 08, 2024

The c.1363A>G (p.M455V) alteration is located in exon 15 (coding exon 15) of the PRPF40B gene. This alteration results from a A to G substitution at nucleotide position 1363, causing the methionine (M) at amino acid position 455 to be replaced by a valine (V). 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

0.88

BayesDel_addAF

Benign

0.0095

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.;T

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.7

.;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.5

.;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.30, 0.88

.;B;P

Vest4

0.79

MutPred

0.34

.;.;Gain of catalytic residue at L452 (P = 0.0594);

MVP

0.61

MPC

0.78

ClinPred

0.77

GERP RS

5.0

Varity_R

0.71

gMVP

0.75

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over