8-103400460-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030780.5(SLC25A32):c.899A>G(p.Tyr300Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,614,122 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (103 hom.)
• Consequence: SLC25A32 NM_030780.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.58

Genes affected

SLC25A32 (HGNC:29683): (solute carrier family 25 member 32) This gene encodes a member of the P(I/L)W subfamily of mitochondrial carrier family transport proteins. The encoded protein transports folate across the inner mitochondrial membrane. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.014725447).
• BP6: Variant 8-103400460-T-C is Benign according to our data. Variant chr8-103400460-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 772905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00294 (448/152356) while in subpopulation SAS AF= 0.0394 (190/4828). AF 95% confidence interval is 0.0348. There are 8 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A32	NM_030780.5	c.899A>G	p.Tyr300Cys	missense_variant	7/7	ENST00000297578.9
SLC25A32	NR_102337.2	n.983A>G		non_coding_transcript_exon_variant	6/6
SLC25A32	NR_102338.2	n.1178A>G		non_coding_transcript_exon_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A32	ENST00000297578.9	c.899A>G	p.Tyr300Cys	missense_variant	7/7	1	NM_030780.5	P1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152238 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00686 AC: 1724 AN: 251360 Hom.: 27 AF XY: 0.00805 AC XY: 1093 AN XY: 135850

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0305

Gnomad SAS exome AF: 0.0323

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00335 AC: 4892 AN: 1461766 Hom.: 103 Cov.: 31 AF XY: 0.00429 AC XY: 3123 AN XY: 727190

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0202

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000433

Gnomad4 OTH exome AF: 0.00742

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152356 Hom.: 8 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74506

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.0304

Gnomad4 SAS AF: 0.0394

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00241 Hom.: 12

Bravo AF: 0.00217

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00749 AC: 909

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

SLC25A32-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Exercise intolerance, riboflavin-responsive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.015	T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.1	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.5	D;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.88
MVP		1.0
MPC		1.1
ClinPred		0.21	T
GERP RS		5.7
Varity_R		0.83
gMVP		0.96

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: rs141856398; hg19: chr8-104412688;