6-46655961-T-C

Variant names:

• chr6-46655961-T-C
• rs3757241
• NM_004277.5:c.225T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004277.5(SLC25A27):​c.225T>C​(p.Ala75Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 1,613,510 control chromosomes in the GnomAD database, including 545,878 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.85 (55768 hom., cov: 30)
  • Exomes 𝑓: 0.82 (490110 hom.)
• Consequence: SLC25A27 NM_004277.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 28 publications found

Genes affected

SLC25A27 (HGNC:21065): (solute carrier family 25 member 27) Mitochondrial uncoupling proteins (UCP) are members of the larger family of mitochondrial anion carrier proteins (MACP). UCPs separate oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as the mitochondrial proton leak. UCPs facilitate the transfer of anions from the inner to the outer mitochondrial membrane and the return transfer of protons from the outer to the inner mitochondrial membrane. They also reduce the mitochondrial membrane potential in mammalian cells. Tissue specificity occurs for the different UCPs and the exact methods of how UCPs transfer H+/OH- are not known. UCPs contain the three homologous protein domains of MACPs. Transcripts of this gene are only detected in brain tissue and are specifically modulated by various environmental conditions. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.175 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A27	NM_004277.5	c.225T>C	p.Ala75Ala	synonymous_variant	Exon 2 of 9	ENST00000371347.10	NP_004268.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A27	ENST00000371347.10	c.225T>C	p.Ala75Ala	synonymous_variant	Exon 2 of 9	1	NM_004277.5	ENSP00000360398.3
SLC25A27	ENST00000411689.6	c.225T>C	p.Ala75Ala	synonymous_variant	Exon 2 of 7	1		ENSP00000412024.2

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129640 AN: 151924 Hom.: 55710 Cov.: 30

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.852

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.764

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.806

Gnomad OTH AF: 0.842

GnomAD2 exomes AF: 0.830 AC: 206797 AN: 249230 AF XY: 0.828

Gnomad AFR exome AF: 0.955

Gnomad AMR exome AF: 0.856

Gnomad ASJ exome AF: 0.824

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.757

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.818 AC: 1195834 AN: 1461468 Hom.: 490110 Cov.: 47 AF XY: 0.820 AC XY: 595915 AN XY: 727022

African (AFR) AF: 0.957 AC: 32031 AN: 33460

American (AMR) AF: 0.854 AC: 38196 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 21647 AN: 26128

East Asian (EAS) AF: 0.886 AC: 35141 AN: 39678

South Asian (SAS) AF: 0.875 AC: 75431 AN: 86226

European-Finnish (FIN) AF: 0.757 AC: 40441 AN: 53396

Middle Eastern (MID) AF: 0.861 AC: 4965 AN: 5768

European-Non Finnish (NFE) AF: 0.808 AC: 897867 AN: 1111730

Other (OTH) AF: 0.830 AC: 50115 AN: 60378

GnomAD4 genome AF: 0.853 AC: 129757 AN: 152042 Hom.: 55768 Cov.: 30 AF XY: 0.853 AC XY: 63399 AN XY: 74304

African (AFR) AF: 0.954 AC: 39582 AN: 41482

American (AMR) AF: 0.852 AC: 13017 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2857 AN: 3468

East Asian (EAS) AF: 0.885 AC: 4561 AN: 5154

South Asian (SAS) AF: 0.891 AC: 4291 AN: 4814

European-Finnish (FIN) AF: 0.764 AC: 8053 AN: 10542

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.806 AC: 54808 AN: 67996

Other (OTH) AF: 0.842 AC: 1778 AN: 2112

Alfa AF: 0.820 Hom.: 202332

Bravo AF: 0.857

Asia WGS AF: 0.901 AC: 3133 AN: 3478

EpiCase AF: 0.802

EpiControl AF: 0.803

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.75
PhyloP100		0.17
Mutation Taster		=299/1	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: rs3757241; hg19: chr6-46623698; COSMIC: COSV107289992; COSMIC: COSV107289992;