8-131959603-A-T

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.795A>T(p.Lys265Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,611,984 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (47 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (40 hom.)
• Consequence: EFR3A NM_015137.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.382

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 (MetaRNN=0.0045548677).
• BP6: Variant 8-131959603-A-T is Benign according to our data. Variant chr8-131959603-A-T is described in ClinVar as [Benign]. Clinvar id is 3060862.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 (2140/152290) while in subpopulation AFR AF= 0.0485 (2016/41544). AF 95% confidence interval is 0.0468. There are 47 homozygotes in gnomad4. There are 1000 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.795A>T	p.Lys265Asn	missense_variant	8/23	ENST00000254624.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFR3A	ENST00000254624.10	c.795A>T	p.Lys265Asn	missense_variant	8/23	1	NM_015137.6	P3
EFR3A	ENST00000519656.1	c.687A>T	p.Lys229Asn	missense_variant	8/23	1		A1
EFR3A	ENST00000637848.1	c.876A>T	p.Lys292Asn	missense_variant	8/23	5

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2138 AN: 152174 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

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: 0.0101

GnomAD3 exomes AF: 0.00359 AC: 897 AN: 250032 Hom.: 18 AF XY: 0.00264 AC XY: 357 AN XY: 135126

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00394

GnomAD4 exome AF: 0.00154 AC: 2243 AN: 1459694 Hom.: 40 Cov.: 30 AF XY: 0.00134 AC XY: 976 AN XY: 726056

Gnomad4 AFR exome AF: 0.0482

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000213

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.0141 AC: 2140 AN: 152290 Hom.: 47 Cov.: 33 AF XY: 0.0134 AC XY: 1000 AN XY: 74472

Gnomad4 AFR AF: 0.0485

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: 0.00996

Alfa AF: 0.00177 Hom.: 1

Bravo AF: 0.0153

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0459 AC: 202

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00416 AC: 505

Asia WGS AF: 0.00145 AC: 5 AN: 3464

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.012	T;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	T;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.083
Sift	Benign	0.036	D;.;D
Sift4G	Benign	0.32	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.19
MutPred		0.32		Loss of methylation at K265 (P = 0.0176);.;.;
MVP		0.44
MPC		0.069
ClinPred		0.0094	T
GERP RS		1.7
Varity_R		0.075
gMVP		0.23

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: rs61740223; hg19: chr8-132971850; COSMIC: COSV105034247;