chr12-49642274-A-G

Position:

• chr12-49642274-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001031698.3(PRPF40B):​c.1924A>G​(p.Lys642Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: PRPF40B NM_001031698.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07775915).
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF40B	NM_001031698.3	c.1924A>G	p.Lys642Glu	missense_variant	20/26	ENST00000548825.7	NP_001026868.2
FMNL3	NM_175736.5	c.*3541T>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	c.1924A>G	p.Lys642Glu	missense_variant	20/26	5	NM_001031698.3	ENSP00000448073	P3
FMNL3	ENST00000335154.10	c.*3541T>C		3_prime_UTR_variant	26/26	1	NM_175736.5	ENSP00000335655

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000264 AC: 66 AN: 249796 Hom.: 0 AF XY: 0.000281 AC XY: 38 AN XY: 135138

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000713

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000157 AC: 229 AN: 1461798 Hom.: 1 Cov.: 31 AF XY: 0.000177 AC XY: 129 AN XY: 727208

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74422

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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

May 24, 2024

The c.1858A>G (p.K620E) alteration is located in exon 19 (coding exon 19) of the PRPF40B gene. This alteration results from a A to G substitution at nucleotide position 1858, causing the lysine (K) at amino acid position 620 to be replaced by a glutamic acid (E). 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	0.93
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	.;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	.;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	.;D;D
Sift4G	Benign	0.10	T;T;T
Polyphen		1.0, 0.76	.;D;P
Vest4		0.63
MVP		0.39
MPC		0.92
ClinPred		0.071	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs201177913; hg19: chr12-50036057;