11-65376495-C-T

Variant names:

• chr11-65376495-C-T
• rs1161832436
• NM_182556.4:c.779G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182556.4(SLC25A45):​c.779G>A​(p.Arg260Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,064 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: SLC25A45 NM_182556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100
• Publications: 0 publications found

Genes affected

SLC25A45 (HGNC:27442): (solute carrier family 25 member 45) Predicted to enable acyl carnitine transmembrane transporter activity. Predicted to be involved in acyl carnitine transport and amino acid transport. Predicted to be located in mitochondrial inner membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

FRMD8 (HGNC:25462): (FERM domain containing 8) Involved in positive regulation of tumor necrosis factor production. Located in several cellular components, including centriolar satellite; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182556.4. 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
	SLC25A45	NM_182556.4	MANE Select	c.779G>A	p.Arg260Gln	missense	Exon 7 of 7	NP_872362.4	Q8N413-1
	SLC25A45	NM_001352381.2		c.779G>A	p.Arg260Gln	missense	Exon 6 of 6	NP_001339310.2	Q8N413-1
	SLC25A45	NM_001278250.3		c.707G>A	p.Arg236Gln	missense	Exon 5 of 5	NP_001265179.3	Q8N413-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A45	ENST00000398802.6	TSL:5 MANE Select	c.779G>A	p.Arg260Gln	missense	Exon 7 of 7	ENSP00000381782.1	Q8N413-1
	SLC25A45	ENST00000534028.5	TSL:1	c.707G>A	p.Arg236Gln	missense	Exon 5 of 5	ENSP00000431769.1	Q8N413-4
	SLC25A45	ENST00000294187.10	TSL:1	c.653G>A	p.Arg218Gln	missense	Exon 6 of 6	ENSP00000294187.6	Q8N413-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247930 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727226

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: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

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

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000660 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	Benign	0.16
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.026	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.010
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.35
MutPred		0.62		Loss of methylation at R260 (P = 0.0029)
MVP		0.34
MPC		0.28
ClinPred		0.79	D
GERP RS		3.8
Varity_R		0.26
gMVP		0.57
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1161832436; hg19: chr11-65143966;