rs140131797

Variant names:

• chr12-31667910-G-A
• rs140131797
• NM_001135863.2:c.709G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001135863.2(ETFBKMT):​c.709G>A​(p.Val237Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,614,166 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: ETFBKMT NM_001135863.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94
• Publications: 4 publications found

Genes affected

ETFBKMT (HGNC:28739): (electron transfer flavoprotein subunit beta lysine methyltransferase) Enables heat shock protein binding activity and protein-lysine N-methyltransferase activity. Involved in negative regulation of electron transfer activity; negative regulation of fatty acid beta-oxidation using acyl-CoA dehydrogenase; and peptidyl-lysine trimethylation. Located in mitochondrial matrix. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007243067).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135863.2. 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
	ETFBKMT	NM_001135863.2	MANE Select	c.709G>A	p.Val237Ile	missense	Exon 4 of 4	NP_001129335.1	Q8IXQ9
	ETFBKMT	NM_001135864.2		c.709G>A	p.Val237Ile	missense	Exon 4 of 4	NP_001129336.1	Q8IXQ9
	ETFBKMT	NM_173802.4		c.709G>A	p.Val237Ile	missense	Exon 4 of 4	NP_776163.1	Q8IXQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFBKMT	ENST00000357721.3	TSL:1 MANE Select	c.709G>A	p.Val237Ile	missense	Exon 4 of 4	ENSP00000350353.3	Q8IXQ9
	ETFBKMT	ENST00000395763.7	TSL:1	c.709G>A	p.Val237Ile	missense	Exon 4 of 4	ENSP00000379112.3	Q8IXQ9
	ETFBKMT	ENST00000538463.5	TSL:1	c.709G>A	p.Val237Ile	missense	Exon 5 of 5	ENSP00000441421.1	Q8IXQ9

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000815 AC: 205 AN: 251474 AF XY: 0.000883

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00183 AC: 2668 AN: 1461884 Hom.: 3 Cov.: 33 AF XY: 0.00174 AC XY: 1266 AN XY: 727248

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000335 AC: 15 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

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

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00227 AC: 2521 AN: 1112002

Other (OTH) AF: 0.00167 AC: 101 AN: 60396

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74472

African (AFR) AF: 0.000337 AC: 14 AN: 41562

American (AMR) AF: 0.000392 AC: 6 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68016

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00130 Hom.: 0

Bravo AF: 0.000994

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00178

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	0.081
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.83
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.017
Sift	Benign	0.23	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.068
MVP		0.014
MPC		0.023
ClinPred		0.00064	T
GERP RS		2.6
Varity_R		0.039
gMVP		0.42
Mutation Taster		=98/2	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: rs140131797; hg19: chr12-31820844; COSMIC: COSV99861369; COSMIC: COSV99861369;