8-23571446-C-T

Variant names:

• chr8-23571446-C-T
• rs1328077616
• NM_016612.4:c.608C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016612.4(SLC25A37):​c.608C>T​(p.Thr203Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,712 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: SLC25A37 NM_016612.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 3 publications found

Genes affected

SLC25A37 (HGNC:29786): (solute carrier family 25 member 37) SLC25A37 is a solute carrier localized in the mitochondrial inner membrane. It functions as an essential iron importer for the synthesis of mitochondrial heme and iron-sulfur clusters (summary by Chen et al., 2009 [PubMed 19805291]).[supplied by OMIM, Jan 2011]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016612.4. 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
	SLC25A37	NM_016612.4	MANE Select	c.608C>T	p.Thr203Met	missense	Exon 4 of 4	NP_057696.2	Q9NYZ2-1
	SLC25A37	NM_001317813.2		c.392C>T	p.Thr131Met	missense	Exon 5 of 5	NP_001304742.1
	SLC25A37	NM_001317814.2		c.392C>T	p.Thr131Met	missense	Exon 5 of 5	NP_001304743.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A37	ENST00000519973.6	TSL:1 MANE Select	c.608C>T	p.Thr203Met	missense	Exon 4 of 4	ENSP00000429200.1	Q9NYZ2-1
	SLC25A37	ENST00000290075.10	TSL:1	n.*617C>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000290075.6	Q9NYZ2-2
	SLC25A37	ENST00000518881.5	TSL:1	n.2629C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249190 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461712 Hom.: 1 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727136

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111868

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.81		Loss of catalytic residue at T203 (P = 0.0458)
MVP		0.89
MPC		1.2
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.77
Mutation Taster		=52/48	polymorphism

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: rs1328077616; hg19: chr8-23428959; COSMIC: COSV51564866; COSMIC: COSV51564866;