Genetic Variant SLC25A16:p.Arg31His (chr10-68527284-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PM5PP2BP4

The NM_152707.4(SLC25A16):c.92G>A(p.Arg31His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC25A16
NM_152707.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.99

Publications

2 publications found

Variant links:

Genes affected

SLC25A16 (HGNC:10986): (solute carrier family 25 member 16) This gene encodes a protein that contains three tandemly repeated mitochondrial carrier protein domains. The encoded protein is localized in the inner membrane and facilitates the rapid transport and exchange of molecules between the cytosol and the mitochondrial matrix space. This gene has a possible role in Graves' disease. [provided by RefSeq, Jul 2008]

SLC25A16 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-68527284-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 545498.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.57984 (below the threshold of 3.09). Trascript score misZ: -0.19574 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.30903822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A16	NM_152707.4 link	c.92G>A	p.Arg31His	missense_variant	Exon 1 of 9	ENST00000609923.6	NP_689920.1	P16260

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC25A16	ENST00000609923.6 link	c.92G>A	p.Arg31His	missense_variant	Exon 1 of 9	1	NM_152707.4	ENSP00000476815.1	P16260
SLC25A16	ENST00000493963.5 link	n.92G>A		non_coding_transcript_exon_variant	Exon 1 of 10	1		ENSP00000476283.1	V9GY06
SLC25A16	ENST00000491102.2 link	n.92G>A		non_coding_transcript_exon_variant	Exon 1 of 4	4		ENSP00000476555.1	V9GYA5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1395900

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30888

American (AMR)

AF:

0.00

AC:

AN:

35588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25000

East Asian (EAS)

AF:

0.00

AC:

AN:

35266

South Asian (SAS)

AF:

0.00

AC:

AN:

79220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5682

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1077826

Other (OTH)

AF:

0.00

AC:

AN:

57836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.032

Eigen

Benign

0.017

Eigen_PC

Benign

0.025

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.81

PhyloP100

2.0

PrimateAI

Pathogenic

0.89

Sift4G

Uncertain

0.022

Polyphen

1.0

Vest4

0.19

MutPred

0.46

Loss of solvent accessibility (P = 0.0128);

MVP

0.51

MPC

0.42

ClinPred

0.85

GERP RS

3.5

PromoterAI

-0.055

Neutral

(source)

Varity_R

0.12

gMVP

0.23

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over