rs34400381

Variant names:

• chr11-65376421-G-A
• rs34400381
• NM_182556.4:c.853C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_182556.4(SLC25A45):​c.853C>T​(p.Arg285Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0302 in 1,613,676 control chromosomes in the GnomAD database, including 911 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.024 (61 hom., cov: 33)
  • Exomes 𝑓: 0.031 (850 hom.)
• Consequence: SLC25A45 NM_182556.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 22 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027039945).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3664/152380) while in subpopulation NFE AF = 0.0347 (2364/68038). AF 95% confidence interval is 0.0336. There are 61 homozygotes in GnomAd4. There are 1861 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A45	NM_182556.4	c.853C>T	p.Arg285Cys	missense_variant	Exon 7 of 7	ENST00000398802.6	NP_872362.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A45	ENST00000398802.6	c.853C>T	p.Arg285Cys	missense_variant	Exon 7 of 7	5	NM_182556.4	ENSP00000381782.1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3666 AN: 152262 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00593

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0618

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0260 AC: 6475 AN: 248858 AF XY: 0.0267

Gnomad AFR exome AF: 0.00634

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0669

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0383

GnomAD4 exome AF: 0.0308 AC: 45016 AN: 1461296 Hom.: 850 Cov.: 31 AF XY: 0.0303 AC XY: 22038 AN XY: 726836

African (AFR) AF: 0.00556 AC: 186 AN: 33478

American (AMR) AF: 0.0149 AC: 666 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0201 AC: 525 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00395 AC: 341 AN: 86256

European-Finnish (FIN) AF: 0.0652 AC: 3479 AN: 53346

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5768

European-Non Finnish (NFE) AF: 0.0341 AC: 37951 AN: 1111568

Other (OTH) AF: 0.0287 AC: 1733 AN: 60370

GnomAD4 genome AF: 0.0240 AC: 3664 AN: 152380 Hom.: 61 Cov.: 33 AF XY: 0.0250 AC XY: 1861 AN XY: 74512

African (AFR) AF: 0.00591 AC: 246 AN: 41600

American (AMR) AF: 0.0159 AC: 243 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 71 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.0618 AC: 656 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2364 AN: 68038

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0291 Hom.: 238

Bravo AF: 0.0209

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0361 AC: 139

ESP6500AA AF: 0.00739 AC: 30

ESP6500EA AF: 0.0342 AC: 286

ExAC AF: 0.0262 AC: 3166

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0321

EpiControl AF: 0.0313

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;T;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.87	.;D;D;D;D
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.9	M;.;M;.;.
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.99	D;D;D;.;D
Vest4		0.024
MPC		0.65
ClinPred		0.038	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.70
Mutation Taster		=99/1	polymorphism (auto)

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: rs34400381; hg19: chr11-65143892;