22-19176172-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005984.5(SLC25A1):c.894T>C(p.Asp298=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00391 in 1,613,856 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (20 hom.)
• Consequence: SLC25A1 NM_005984.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.587

Genes affected

SLC25A1 (HGNC:10979): (solute carrier family 25 member 1) This gene encodes a member of the mitochondrial carrier subfamily of solute carrier proteins. Members of this family include nuclear-encoded transporters that translocate small metabolites across the mitochondrial membrane. This protein regulates the movement of citrate across the inner membranes of the mitochondria. Mutations in this gene have been associated with combined D-2- and L-2-hydroxyglutaric aciduria. Pseudogenes of this gene have been identified on chromosomes 7, 11, 16, and 19. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 22-19176172-A-G is Benign according to our data. Variant chr22-19176172-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.587 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00352 (536/152242) while in subpopulation AMR AF= 0.00804 (123/15296). AF 95% confidence interval is 0.00689. There are 3 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A1	NM_005984.5	c.894T>C	p.Asp298=	synonymous_variant	9/9	ENST00000215882.10
SLC25A1	NM_001256534.2	c.915T>C	p.Asp305=	synonymous_variant	8/8
SLC25A1	NM_001287387.2	c.585T>C	p.Asp195=	synonymous_variant	9/9
SLC25A1	NR_046298.3	n.818T>C		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A1	ENST00000215882.10	c.894T>C	p.Asp298=	synonymous_variant	9/9	1	NM_005984.5	P1
SLC25A1	ENST00000451283.5	c.585T>C	p.Asp195=	synonymous_variant	9/9	2
SLC25A1	ENST00000470922.5	n.1036T>C		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152124 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00354 AC: 890 AN: 251308 Hom.: 7 AF XY: 0.00378 AC XY: 513 AN XY: 135866

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00395 AC: 5769 AN: 1461614 Hom.: 20 Cov.: 33 AF XY: 0.00412 AC XY: 2995 AN XY: 727124

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00479

Gnomad4 ASJ exome AF: 0.00218

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00282

Gnomad4 FIN exome AF: 0.000545

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00510

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152242 Hom.: 3 Cov.: 33 AF XY: 0.00325 AC XY: 242 AN XY: 74430

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00510

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00416 Hom.: 2

Bravo AF: 0.00451

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SLC25A1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

SLC25A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2020

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.5
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

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: rs144180074; hg19: chr22-19163685;