rs3765166

Positions:

• chr2-171837270-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000422440.7(SLC25A12):​c.466-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,613,082 control chromosomes in the GnomAD database, including 55,169 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4195 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50974 hom.)
• Consequence: SLC25A12 ENST00000422440.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001212
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.360

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 (BayesDel_noAF=-0.77).
• BP6: Variant 2-171837270-G-A is Benign according to our data. Variant chr2-171837270-G-A is described in ClinVar as [Benign]. Clinvar id is 332344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A12	NM_003705.5	c.466-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000422440.7	NP_003696.2
SLC25A12	XM_047446142.1	c.193-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047302098.1
SLC25A12	NR_047549.2	n.380-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A12	ENST00000422440.7	c.466-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003705.5	ENSP00000388658	P1
SLC25A12	ENST00000263812.8	c.*86-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000263812
SLC25A12	ENST00000426896.5	c.570-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		2		ENSP00000413968
SLC25A12	ENST00000475360.6	c.*183-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000437845

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32573 AN: 151976 Hom.: 4198 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.222

GnomAD3 exomes AF: 0.264 AC: 66341 AN: 251024 Hom.: 10260 AF XY: 0.270 AC XY: 36576 AN XY: 135674

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.575

Gnomad SAS exome AF: 0.306

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.256 AC: 374156 AN: 1460988 Hom.: 50974 Cov.: 34 AF XY: 0.258 AC XY: 187549 AN XY: 726846

Gnomad4 AFR exome AF: 0.0916

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.562

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.257

GnomAD4 genome AF: 0.214 AC: 32554 AN: 152094 Hom.: 4195 Cov.: 32 AF XY: 0.218 AC XY: 16196 AN XY: 74346

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.572

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.219

Alfa AF: 0.246 Hom.: 11165

Bravo AF: 0.204

Asia WGS AF: 0.356 AC: 1241 AN: 3476

EpiCase AF: 0.248

EpiControl AF: 0.251

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.3
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.016
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: rs3765166; hg19: chr2-172693780; COSMIC: COSV55536150; COSMIC: COSV55536150;