8-131953920-T-G

Variant names:

• chr8-131953920-T-G
• rs149106647
• NM_015137.6:c.591T>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015137.6(EFR3A):​c.591T>G​(p.Ile197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,572,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I197F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: EFR3A NM_015137.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.134

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009498179).
• BP6: Variant 8-131953920-T-G is Benign according to our data. Variant chr8-131953920-T-G is described in ClinVar as [Benign]. Clinvar id is 3034454.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00117 (1665/1420118) while in subpopulation MID AF= 0.0273 (156/5712). AF 95% confidence interval is 0.0238. There are 9 homozygotes in gnomad4_exome. There are 863 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFR3A	NM_015137.6	c.591T>G	p.Ile197Met	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.591T>G	p.Ile197Met	missense_variant	Exon 6 of 23	1	NM_015137.6	ENSP00000254624.5
EFR3A	ENST00000519656.1	c.483T>G	p.Ile161Met	missense_variant	Exon 6 of 23	1		ENSP00000428086.1
EFR3A	ENST00000637848.1	c.672T>G	p.Ile224Met	missense_variant	Exon 6 of 23	5		ENSP00000490312.1
EFR3A	ENST00000522709.5	c.*84T>G		downstream_gene_variant		5		ENSP00000430512.1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000868

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00160 AC: 306 AN: 190876 Hom.: 0 AF XY: 0.00174 AC XY: 176 AN XY: 101108

Gnomad AFR exome AF: 0.000558

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00200

Gnomad FIN exome AF: 0.0000534

Gnomad NFE exome AF: 0.000959

Gnomad OTH exome AF: 0.00418

GnomAD4 exome AF: 0.00117 AC: 1665 AN: 1420118 Hom.: 9 Cov.: 33 AF XY: 0.00123 AC XY: 863 AN XY: 702448

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.0000391

Gnomad4 NFE exome AF: 0.000719

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.00109 AC XY: 81 AN XY: 74370

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000868

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00177 Hom.: 1

Bravo AF: 0.00131

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00126 AC: 151

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EFR3A-related disorder Benign:1

Jul 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0095	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	N;.;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0040	D;.;D
Polyphen		1.0	D;.;.
Vest4		0.63
MVP		0.70
MPC		0.37
ClinPred		0.042	T
GERP RS		0.50
Varity_R		0.39
gMVP		0.60

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: rs149106647; hg19: chr8-132966167;