12-49642247-G-T

Position:

• chr12-49642247-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001031698.3(PRPF40B):​c.1897G>T​(p.Ala633Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPF40B NM_001031698.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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]

ACMG classification

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, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF40B	NM_001031698.3	c.1897G>T	p.Ala633Ser	missense_variant	20/26	ENST00000548825.7	NP_001026868.2
FMNL3	NM_175736.5	c.*3568C>A		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	c.1897G>T	p.Ala633Ser	missense_variant	20/26	5	NM_001031698.3	ENSP00000448073	P3
FMNL3	ENST00000335154.10	c.*3568C>A		3_prime_UTR_variant	26/26	1	NM_175736.5	ENSP00000335655

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.1831G>T (p.A611S) alteration is located in exon 19 (coding exon 19) of the PRPF40B gene. This alteration results from a G to T substitution at nucleotide position 1831, causing the alanine (A) at amino acid position 611 to be replaced by a serine (S). 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	0.60
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.7	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.9	.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	.;D;D
Sift4G	Uncertain	0.052	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.76
MutPred		0.46		.;.;Gain of phosphorylation at A611 (P = 0.0021);
MVP		0.52
MPC		0.76
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.39
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-50036030;