chr2-152657909-T-C

Position:

• chr2-152657909-T-C

Variant summary

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

The NM_001365597.4(PRPF40A):​c.2806A>G​(p.Lys936Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,452,216 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PRPF40A NM_001365597.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

Genes affected

PRPF40A (HGNC:16463): (pre-mRNA processing factor 40 homolog A) Enables RNA binding activity. Involved in several processes, including cytoskeleton organization; regulation of cell shape; and regulation of cytokinesis. Located in nuclear matrix and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18382451).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPF40A	NM_001365597.4	c.2806A>G	p.Lys936Glu	missense_variant	25/26	ENST00000545856.8	NP_001352526.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPF40A	ENST00000545856.8	c.2806A>G	p.Lys936Glu	missense_variant	25/26	1	NM_001365597.4	ENSP00000444656.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1452216 Hom.: 0 Cov.: 30 AF XY: 0.00000970 AC XY: 7 AN XY: 721634

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

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

Jun 16, 2024

The c.2680A>G (p.K894E) alteration is located in exon 25 (coding exon 25) of the PRPF40A gene. This alteration results from a A to G substitution at nucleotide position 2680, causing the lysine (K) at amino acid position 894 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
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Benign	0.69
Eigen	Benign	-0.096
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.17
MVP		0.42
MPC		0.86
ClinPred		0.64	D
GERP RS		5.3
gMVP		0.14

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

Other links and lift over

dbSNP: rs759084868; hg19: chr2-153514423;