11-793555-G-C

Position:

chr11-793555-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001425344.1(SLC25A22):c.-52C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000428 in 1,613,500 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: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SLC25A22
NM_001425344.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.72

Variant links:

Genes affected

SLC25A22 (HGNC:19954): (solute carrier family 25 member 22) This gene encodes a mitochondrial glutamate carrier. Mutations in this gene are associated with early infantile epileptic encephalopathy. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jul 2010]

SLC25A22 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060960114).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000236 (36/152252) while in subpopulation AFR AF= 0.000746 (31/41546). AF 95% confidence interval is 0.000539. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A22	NM_001191061.2 link	c.267C>G	p.Phe89Leu	missense_variant	5/10	ENST00000628067.3	NP_001177990.1	Q9H936

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A22	ENST00000628067.3 link	c.267C>G	p.Phe89Leu	missense_variant	5/10	1	NM_001191061.2	ENSP00000486058.1		Q9H936

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250694

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135662

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461248

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726930

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000828

GnomAD4 genome

AF:

0.000236

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000234

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.267C>G (p.F89L) alteration is located in exon 5 (coding exon 4) of the SLC25A22 gene. This alteration results from a C to G substitution at nucleotide position 267, causing the phenylalanine (F) at amino acid position 89 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Early infantile epileptic encephalopathy with suppression bursts

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the SLC25A22 protein (p.Phe89Leu). This variant is present in population databases (rs143064022, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with SLC25A22-related conditions. ClinVar contains an entry for this variant (Variation ID: 207157). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC25A22 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

A variant of uncertain significance has been identified in the SLC25A22 gene. The F89L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 21/23990 (0.09%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. However, the F89L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Early myoclonic encephalopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;T;T;.;.;.;.;.;.;.;.;T;T;T;.;.;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.0036

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.073

MetaRNN

Benign

0.061

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.92

L;L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

D;.;D;D;.;D;.;D;D;D;.;D;D;.;D;D;.

REVEL

Uncertain

0.49

Sift

Benign

0.17

T;.;T;D;.;T;.;T;T;T;.;T;T;.;T;T;.

Sift4G

Benign

0.58

T;T;T;T;T;.;T;T;T;.;T;.;.;.;.;.;.

Polyphen

0.028

B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.78

MutPred

0.43

Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);.;Gain of disorder (P = 0.1762);.;Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);Gain of disorder (P = 0.1762);

MVP

0.61

MPC

0.49

ClinPred

0.10

GERP RS

3.5

Varity_R

0.59

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over