NM_004453.4:c.1533T>C

Variant names:

• chr4-158706693-T-C
• rs77484245
• NM_004453.4:c.1533T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004453.4(ETFDH):​c.1533T>C​(p.Asp511Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,614,166 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (58 hom.)
• Consequence: ETFDH NM_004453.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.134
• Publications: 2 publications found

Genes affected

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ETFDH Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-158706693-T-C is Benign according to our data. Variant chr4-158706693-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.134 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00532 (811/152330) while in subpopulation NFE AF = 0.00541 (368/68030). AF 95% confidence interval is 0.00495. There are 7 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004453.4. 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
	ETFDH	NM_004453.4	MANE Select	c.1533T>C	p.Asp511Asp	synonymous	Exon 12 of 13	NP_004444.2	Q16134-1
	ETFDH	NM_001281737.2		c.1392T>C	p.Asp464Asp	synonymous	Exon 11 of 12	NP_001268666.1	Q16134-3
	ETFDH	NM_001281738.1		c.1350T>C	p.Asp450Asp	synonymous	Exon 10 of 11	NP_001268667.1	B4DEQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ETFDH	ENST00000511912.6	TSL:1 MANE Select	c.1533T>C	p.Asp511Asp	synonymous	Exon 12 of 13	ENSP00000426638.1	Q16134-1
	ETFDH	ENST00000506422.1	TSL:1	n.503T>C		non_coding_transcript_exon	Exon 4 of 5
	ETFDH	ENST00000684622.1		c.1533T>C	p.Asp511Asp	synonymous	Exon 12 of 14	ENSP00000507546.1	A0A804HJK8

Frequencies

GnomAD3 genomes AF: 0.00533 AC: 811 AN: 152212 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00657 AC: 1653 AN: 251440 AF XY: 0.00673

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00615

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0318

Gnomad NFE exome AF: 0.00578

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00608 AC: 8894 AN: 1461836 Hom.: 58 Cov.: 31 AF XY: 0.00592 AC XY: 4307 AN XY: 727224

African (AFR) AF: 0.000777 AC: 26 AN: 33476

American (AMR) AF: 0.00208 AC: 93 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 125 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00329 AC: 284 AN: 86258

European-Finnish (FIN) AF: 0.0303 AC: 1618 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00575 AC: 6393 AN: 1111968

Other (OTH) AF: 0.00581 AC: 351 AN: 60394

GnomAD4 genome AF: 0.00532 AC: 811 AN: 152330 Hom.: 7 Cov.: 32 AF XY: 0.00646 AC XY: 481 AN XY: 74502

African (AFR) AF: 0.000794 AC: 33 AN: 41574

American (AMR) AF: 0.00105 AC: 16 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.0329 AC: 350 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68030

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00523 Hom.: 4

Bravo AF: 0.00307

EpiCase AF: 0.00469

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple acyl-CoA dehydrogenase deficiency (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.97
DANN	Benign	0.60
PhyloP100		-0.13
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: rs77484245; hg19: chr4-159627845;