14-105314544-T-C

Position:

• chr14-105314544-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000325438(PACS2):​c.-375T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 144,122 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (81 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PACS2 ENST00000325438 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

Genes affected

PACS2 (HGNC:23794): (phosphofurin acidic cluster sorting protein 2) Predicted to enable transmembrane transporter binding activity. Involved in endoplasmic reticulum calcium ion homeostasis; mitochondrion-endoplasmic reticulum membrane tethering; and protein localization to plasma membrane. Acts upstream of or within protein localization to phagophore assembly site. Located in endoplasmic reticulum and mitochondrion. Implicated in developmental and epileptic encephalopathy 66. [provided by Alliance of Genome Resources, Apr 2022]

BRF1 (HGNC:11551): (BRF1 RNA polymerase III transcription initiation factor subunit) This gene encodes one of the three subunits of the RNA polymerase III transcription factor complex. This complex plays a central role in transcription initiation by RNA polymerase III on genes encoding tRNA, 5S rRNA, and other small structural RNAs. The gene product belongs to the TF2B family. Several alternatively spliced variants encoding different isoforms, that function at different promoters transcribed by RNA polymerase III, have been identified. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 14-105314544-T-C is Benign according to our data. Variant chr14-105314544-T-C is described in ClinVar as [Benign]. Clinvar id is 1272011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PACS2	NM_001243127.3	c.-83+13565T>C		intron_variant			NP_001230056.1
BRF1	NM_001242786.2	c.-162+778A>G		intron_variant			NP_001229715.1
BRF1	NM_001242787.2	c.-162+778A>G		intron_variant			NP_001229716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PACS2	ENST00000325438	c.-375T>C		5_prime_UTR_variant	1/24	1		ENSP00000321834.8
PACS2	ENST00000430725.6	c.-83+13565T>C		intron_variant		1		ENSP00000393524.2
BRF1	ENST00000440513.7	c.-162+778A>G		intron_variant		2		ENSP00000388877.3

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2661 AN: 144032 Hom.: 80 Cov.: 31

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.00659

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000767

Gnomad OTH AF: 0.0110

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0185 AC: 2663 AN: 144122 Hom.: 81 Cov.: 31 AF XY: 0.0177 AC XY: 1242 AN XY: 70266

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.00570

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0149

Gnomad4 SAS AF: 0.00660

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000767

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0130 Hom.: 6

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.69

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: rs867298388; hg19: chr14-105780881;