NM_001135863.2:c.314+1G>A

Variant names:

• chr12-31662268-G-A
• rs138229541
• NM_001135863.2:c.314+1G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001135863.2(ETFBKMT):​c.314+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,613,484 control chromosomes in the GnomAD database, including 30 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (28 hom.)
• Consequence: ETFBKMT NM_001135863.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.02
• Publications: 8 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-31662268-G-A is Benign according to our data. Variant chr12-31662268-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2642829.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 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.314+1G>A		splice_donor intron	N/A	NP_001129335.1	Q8IXQ9
	ETFBKMT	NM_001135864.2		c.314+1G>A		splice_donor intron	N/A	NP_001129336.1	Q8IXQ9
	ETFBKMT	NM_173802.4		c.314+1G>A		splice_donor intron	N/A	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.314+1G>A		splice_donor intron	N/A	ENSP00000350353.3	Q8IXQ9
	ETFBKMT	ENST00000395763.7	TSL:1	c.314+1G>A		splice_donor intron	N/A	ENSP00000379112.3	Q8IXQ9
	ETFBKMT	ENST00000538463.5	TSL:1	c.314+1G>A		splice_donor intron	N/A	ENSP00000441421.1	Q8IXQ9

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00438 AC: 1097 AN: 250600 AF XY: 0.00452

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00461

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00456 AC: 6660 AN: 1461220 Hom.: 28 Cov.: 31 AF XY: 0.00463 AC XY: 3366 AN XY: 726864

African (AFR) AF: 0.000867 AC: 29 AN: 33460

American (AMR) AF: 0.00512 AC: 229 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000882 AC: 23 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00423 AC: 365 AN: 86244

European-Finnish (FIN) AF: 0.00897 AC: 478 AN: 53294

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5752

European-Non Finnish (NFE) AF: 0.00469 AC: 5215 AN: 1111664

Other (OTH) AF: 0.00419 AC: 253 AN: 60358

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74436

African (AFR) AF: 0.00103 AC: 43 AN: 41562

American (AMR) AF: 0.00576 AC: 88 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.0102 AC: 108 AN: 10604

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00472 AC: 321 AN: 68030

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00392 Hom.: 5

Bravo AF: 0.00341

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.0
GERP RS		4.4
PromoterAI		0.017	Neutral
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138229541; hg19: chr12-31815202; COSMIC: COSV105270575; COSMIC: COSV105270575;