NM_031212.4:c.421G>T

Variant names:

• chr10-99613795-C-A
• rs777994494
• NM_031212.4:c.421G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031212.4(SLC25A28):​c.421G>T​(p.Ala141Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A141T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC25A28 NM_031212.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.54
• Publications: 0 publications found

Genes affected

SLC25A28 (HGNC:23472): (solute carrier family 25 member 28) Predicted to enable ferrous iron transmembrane transporter activity. Predicted to be involved in iron import into the mitochondrion. Predicted to be located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000229278 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031212.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A28	NM_031212.4	MANE Select	c.421G>T	p.Ala141Ser	missense	Exon 2 of 4	NP_112489.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A28	ENST00000370495.6	TSL:1 MANE Select	c.421G>T	p.Ala141Ser	missense	Exon 2 of 4	ENSP00000359526.4	Q96A46-1
	SLC25A28	ENST00000913498.1		c.421G>T	p.Ala141Ser	missense	Exon 2 of 4	ENSP00000583557.1
	SLC25A28	ENST00000966520.1		c.421G>T	p.Ala141Ser	missense	Exon 2 of 3	ENSP00000636579.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.58
Sift	Benign	0.041	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.71
MutPred		0.66		Gain of glycosylation at A141 (P = 0.0016)
MVP		0.61
MPC		2.2
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.87
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs777994494; hg19: chr10-101373552;