8-131946516-A-C

Variant names:

• chr8-131946516-A-C
• rs990812631
• NM_015137.6:c.249A>C

Variant summary

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

The NM_015137.6(EFR3A):​c.249A>C​(p.Gln83His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EFR3A NM_015137.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.528

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=0.33172256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFR3A	NM_015137.6	c.249A>C	p.Gln83His	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.249A>C	p.Gln83His	missense_variant	Exon 4 of 23	1	NM_015137.6	ENSP00000254624.5
EFR3A	ENST00000519656.1	c.141A>C	p.Gln47His	missense_variant	Exon 4 of 23	1		ENSP00000428086.1
EFR3A	ENST00000637848.1	c.330A>C	p.Gln110His	missense_variant	Exon 4 of 23	5		ENSP00000490312.1
EFR3A	ENST00000522709.5	c.141A>C	p.Gln47His	missense_variant	Exon 4 of 6	5		ENSP00000430512.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.249A>C (p.Q83H) alteration is located in exon 4 (coding exon 4) of the EFR3A gene. This alteration results from a A to C substitution at nucleotide position 249, causing the glutamine (Q) at amino acid position 83 to be replaced by a histidine (H). 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	Pathogenic	0.76
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.37	N
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;D;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Uncertain	0.027	D;D;.;D
Polyphen		0.92	P;.;.;.
Vest4		0.81
MutPred		0.33		Gain of catalytic residue at L85 (P = 0.1583);.;.;.;
MVP		0.25
MPC		0.32
ClinPred		0.99	D
GERP RS		-5.7
Varity_R		0.56
gMVP		0.53

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: rs990812631; hg19: chr8-132958763;