8-131953882-C-T

Variant names:

• chr8-131953882-C-T
• rs1818836322
• NM_015137.6:c.553C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015137.6(EFR3A):​c.553C>T​(p.Arg185Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,642 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: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EFR3A NM_015137.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.99

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36628348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFR3A	NM_015137.6	c.553C>T	p.Arg185Trp	missense_variant	Exon 6 of 23	ENST00000254624.10	NP_055952.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFR3A	ENST00000254624.10	c.553C>T	p.Arg185Trp	missense_variant	Exon 6 of 23	1	NM_015137.6	ENSP00000254624.5
EFR3A	ENST00000519656.1	c.445C>T	p.Arg149Trp	missense_variant	Exon 6 of 23	1		ENSP00000428086.1
EFR3A	ENST00000637848.1	c.634C>T	p.Arg212Trp	missense_variant	Exon 6 of 23	5		ENSP00000490312.1
EFR3A	ENST00000522709.5	c.*46C>T		downstream_gene_variant		5		ENSP00000430512.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424642 Hom.: 0 Cov.: 33 AF XY: 0.00000142 AC XY: 1 AN XY: 705162

Gnomad4 AFR exome AF: 0.0000306

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.553C>T (p.R185W) alteration is located in exon 6 (coding exon 6) of the EFR3A gene. This alteration results from a C to T substitution at nucleotide position 553, causing the arginine (R) at amino acid position 185 to be replaced by a tryptophan (W). 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	0.55
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N;.;N
REVEL	Benign	0.18
Sift	Uncertain	0.023	D;.;D
Sift4G	Uncertain	0.025	D;.;D
Polyphen		0.90	P;.;.
Vest4		0.53
MutPred		0.43		Loss of MoRF binding (P = 0.0582);.;.;
MVP		0.65
MPC		0.25
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.20
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1818836322; hg19: chr8-132966129;