rs35565687

chr2-171793655-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003705.5(SLC25A12):c.1418G>A(p.Arg473Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0392 in 1,613,974 control chromosomes in the GnomAD database, including 1,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R473W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.031 (104 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1374 hom.)
• Consequence: SLC25A12 NM_003705.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.30

Genes affected

SLC25A12 (HGNC:10982): (solute carrier family 25 member 12) This gene encodes a calcium-binding mitochondrial carrier protein. The encoded protein localizes to the mitochondria and is involved in the exchange of aspartate for glutamate across the inner mitochondrial membrane. Polymorphisms in this gene may be associated with autism, and mutations in this gene may also be a cause of global cerebral hypomyelination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021488369).
• BP6: Variant 2-171793655-C-T is Benign according to our data. Variant chr2-171793655-C-T is described in ClinVar as [Benign]. Clinvar id is 332339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.031 (4723/152234) while in subpopulation NFE AF= 0.0461 (3137/68020). AF 95% confidence interval is 0.0448. There are 104 homozygotes in gnomad4. There are 2291 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 104 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A12	NM_003705.5	c.1418G>A	p.Arg473Gln	missense_variant	14/18	ENST00000422440.7
SLC25A12	XM_047446142.1	c.1145G>A	p.Arg382Gln	missense_variant	12/16
SLC25A12	NR_047549.2	n.1332G>A		non_coding_transcript_exon_variant	13/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A12	ENST00000422440.7	c.1418G>A	p.Arg473Gln	missense_variant	14/18	1	NM_003705.5	P1
SLC25A12	ENST00000263812.8	c.*1038G>A		3_prime_UTR_variant, NMD_transcript_variant	13/17	2

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4723 AN: 152116 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00659

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0690

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0461

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0326 AC: 8188 AN: 251348 Hom.: 217 AF XY: 0.0319 AC XY: 4332 AN XY: 135846

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00663

Gnomad FIN exome AF: 0.0747

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0409

GnomAD4 exome AF: 0.0400 AC: 58510 AN: 1461740 Hom.: 1374 Cov.: 32 AF XY: 0.0391 AC XY: 28467 AN XY: 727182

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00577

Gnomad4 FIN exome AF: 0.0806

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0310 AC: 4723 AN: 152234 Hom.: 104 Cov.: 32 AF XY: 0.0308 AC XY: 2291 AN XY: 74422

Gnomad4 AFR AF: 0.00657

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.0690

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0418 Hom.: 231

Bravo AF: 0.0267

TwinsUK AF: 0.0475 AC: 176

ALSPAC AF: 0.0457 AC: 176

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0459 AC: 395

ExAC AF: 0.0337 AC: 4093

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0418

EpiControl AF: 0.0420

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.50	D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.27
Sift	Benign	0.053	T
Sift4G	Uncertain	0.025	D
Polyphen		0.75	P
Vest4		0.13
MPC		0.74
ClinPred		0.030	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs35565687; hg19: chr2-172650165;