8-131955765-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015137.6(EFR3A):c.639-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,603,732 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (39 hom.)
• Consequence: EFR3A NM_015137.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004333
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.173

Genes affected

EFR3A (HGNC:28970): (EFR3 homolog A) The protein encoded by this gene is part of a complex that plays a role in maintaining an active pool of phosphatidylinositol 4-kinase (PI4K) at the plasma membrane. This protein is thought to be a peripheral membrane protein that associates with the plasma membrane through palmitoylation. Studies indicate that this gene product plays a role in controlling G protein-coupled receptor (GPCR) activity by affecting receptor phosphorylation. Whole exome sequencing studies have implicated mutations in this gene with autism spectrum disorders. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 8-131955765-T-C is Benign according to our data. Variant chr8-131955765-T-C is described in ClinVar as [Benign]. Clinvar id is 3060704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0141 (2143/152296) while in subpopulation AFR AF= 0.0486 (2019/41568). AF 95% confidence interval is 0.0468. There are 47 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 47 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFR3A	NM_015137.6	c.639-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000254624.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFR3A	ENST00000254624.10	c.639-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015137.6	P3
EFR3A	ENST00000519656.1	c.531-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		A1
EFR3A	ENST00000637848.1	c.720-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0141 AC: 2141 AN: 152178 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00544

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00368 AC: 893 AN: 242538 Hom.: 18 AF XY: 0.00271 AC XY: 355 AN XY: 130870

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000714

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00153 AC: 2217 AN: 1451436 Hom.: 39 Cov.: 30 AF XY: 0.00134 AC XY: 964 AN XY: 721496

Gnomad4 AFR exome AF: 0.0484

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.00324

GnomAD4 genome AF: 0.0141 AC: 2143 AN: 152296 Hom.: 47 Cov.: 33 AF XY: 0.0135 AC XY: 1002 AN XY: 74472

Gnomad4 AFR AF: 0.0486

Gnomad4 AMR AF: 0.00543

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00640 Hom.: 10

Bravo AF: 0.0153

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EFR3A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.1
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.040		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: rs116739700; hg19: chr8-132968012;