8-131953818-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015137.6(EFR3A):c.489G>T(p.Glu163Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,343,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EFR3A NM_015137.6 missense, splice_region
• Scores: Splicing: ADA: 0.1445
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.15

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11440855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFR3A	NM_015137.6	c.489G>T	p.Glu163Asp	missense_variant, splice_region_variant	6/23	ENST00000254624.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFR3A	ENST00000254624.10	c.489G>T	p.Glu163Asp	missense_variant, splice_region_variant	6/23	1	NM_015137.6	P3
EFR3A	ENST00000519656.1	c.381G>T	p.Glu127Asp	missense_variant, splice_region_variant	6/23	1		A1
EFR3A	ENST00000637848.1	c.570G>T	p.Glu190Asp	missense_variant, splice_region_variant	6/23	5
EFR3A	ENST00000522709.5	c.381G>T	p.Glu127Asp	missense_variant, splice_region_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 145526 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000521 AC: 7 AN: 1343620 Hom.: 0 Cov.: 33 AF XY: 0.00000303 AC XY: 2 AN XY: 660068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000190

Gnomad4 OTH exome AF: 0.0000181

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000137 AC: 2 AN: 145622 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70464

Gnomad4 AFR AF: 0.0000254

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EFR3A-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2024

The EFR3A c.489G>T variant is predicted to result in the amino acid substitution p.Glu163Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.011	T;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.2	N;N;.;N
REVEL	Benign	0.079
Sift	Benign	0.12	T;T;.;T
Sift4G	Benign	0.12	T;D;.;T
Polyphen		0.0070	B;.;.;.
Vest4		0.18
MutPred		0.32		Loss of helix (P = 0.1299);.;.;.;
MVP		0.33
MPC		0.056
ClinPred		0.071	T
GERP RS		0.14
Varity_R		0.040
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.34
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: rs1240046828; hg19: chr8-132966065;