8-131946604-C-A

Variant names:

• chr8-131946604-C-A
• NM_015137.6:c.337C>A

Variant summary

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

The NM_015137.6(EFR3A):​c.337C>A​(p.Pro113Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P113Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EFR3A NM_015137.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFR3A	NM_015137.6	c.337C>A	p.Pro113Thr	missense_variant	Exon 4 of 23	ENST00000254624.10	NP_055952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFR3A	ENST00000254624.10	c.337C>A	p.Pro113Thr	missense_variant	Exon 4 of 23	1	NM_015137.6	ENSP00000254624.5
EFR3A	ENST00000519656.1	c.229C>A	p.Pro77Thr	missense_variant	Exon 4 of 23	1		ENSP00000428086.1
EFR3A	ENST00000637848.1	c.418C>A	p.Pro140Thr	missense_variant	Exon 4 of 23	5		ENSP00000490312.1
EFR3A	ENST00000522709.5	c.229C>A	p.Pro77Thr	missense_variant	Exon 4 of 6	5		ENSP00000430512.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451232 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721416

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337C>A (p.P113T) alteration is located in exon 4 (coding exon 4) of the EFR3A gene. This alteration results from a C to A substitution at nucleotide position 337, causing the proline (P) at amino acid position 113 to be replaced by a threonine (T). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.7	D;D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;T;.;D
Sift4G	Benign	0.089	T;T;.;T
Polyphen		0.39	B;.;.;.
Vest4		0.79
MutPred		0.37		Loss of glycosylation at P113 (P = 0.1011);.;.;.;
MVP		0.40
MPC		0.15
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-132958851;