5-141303324-A-C

Variant names:

• chr5-141303324-A-C
• rs3749779
• NM_031947.4:c.542T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031947.4(SLC25A2):​c.542T>G​(p.Val181Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,202 control chromosomes in the GnomAD database, including 1,153 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (137 hom., cov: 32)
  • Exomes 𝑓: 0.012 (1016 hom.)
• Consequence: SLC25A2 NM_031947.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

Genes affected

SLC25A2 (HGNC:22921): (solute carrier family 25 member 2) This intronless gene encodes a protein that localizes to the mitochondrial inner membrane and likely functions as a transporter of small molecules such as ornithine. This gene is located between the protocadherin beta and gamma gene clusters on chromosome 5. [provided by RefSeq, Dec 2014]

TAF7 (HGNC:11541): (TATA-box binding protein associated factor 7) The intronless gene for this transcription coactivator is located between the protocadherin beta and gamma gene clusters on chromosome 5. The protein encoded by this gene is a component of the TFIID protein complex, a complex which binds to the TATA box in class II promoters and recruits RNA polymerase II and other factors. This particular subunit interacts with the largest TFIID subunit, as well as multiple transcription activators. The protein is required for transcription by promoters targeted by RNA polymerase II. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024497807).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0996 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A2	NM_031947.4	c.542T>G	p.Val181Gly	missense_variant	Exon 1 of 1	ENST00000239451.7	NP_114153.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A2	ENST00000239451.7	c.542T>G	p.Val181Gly	missense_variant	Exon 1 of 1	6	NM_031947.4	ENSP00000239451.4
TAF7	ENST00000624699.1	n.128+17194T>G		intron_variant	Intron 1 of 2	3
TAF7	ENST00000686518.1	n.75+17194T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2617 AN: 152202 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0378

Gnomad FIN AF: 0.00301

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0382 AC: 9604 AN: 251392 Hom.: 735 AF XY: 0.0331 AC XY: 4500 AN XY: 135884

Gnomad AFR exome AF: 0.00326

Gnomad AMR exome AF: 0.177

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0952

Gnomad SAS exome AF: 0.0390

Gnomad FIN exome AF: 0.00388

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0118 AC: 17310 AN: 1461882 Hom.: 1016 Cov.: 39 AF XY: 0.0119 AC XY: 8681 AN XY: 727242

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.167

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0944

Gnomad4 SAS exome AF: 0.0378

Gnomad4 FIN exome AF: 0.00348

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0173 AC: 2634 AN: 152320 Hom.: 137 Cov.: 32 AF XY: 0.0200 AC XY: 1489 AN XY: 74474

Gnomad4 AFR AF: 0.00361

Gnomad4 AMR AF: 0.104

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.102

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.00301

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00805 Hom.: 144

Bravo AF: 0.0258

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0319 AC: 3878

Asia WGS AF: 0.0650 AC: 224 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.87	P
Vest4		0.18
MPC		0.82
ClinPred		0.047	T
GERP RS		3.8
Varity_R		0.78
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs3749779; hg19: chr5-140682891; COSMIC: COSV53404269;