chr4-158672031-A-G

Variant names:

• chr4-158672031-A-G
• rs78201564
• ENST00000508836.1:n.225T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000908056.1(ETFDH):​c.-284A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 550,534 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: ETFDH ENST00000908056.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.310
• Publications: 2 publications found

Genes affected

C4orf46 (HGNC:27320): (chromosome 4 open reading frame 46) This gene encodes a small, conserved protein of unknown function that is expressed in a variety of tissues. There are pseudogenes for this gene on chromosomes 6, 8, 16, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-158672031-A-G is Benign according to our data. Variant chr4-158672031-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1212006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1769/152024) while in subpopulation AFR AF = 0.0378 (1568/41438). AF 95% confidence interval is 0.0363. There are 28 homozygotes in GnomAd4. There are 841 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000908056.1. 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
	C4orf46	NR_077234.2		n.26T>C		non_coding_transcript_exon	Exon 1 of 2
	C4orf46	NR_077235.2		n.26T>C		non_coding_transcript_exon	Exon 1 of 2
	C4orf46	NM_001008393.4	MANE Select	c.-230T>C		upstream_gene	N/A	NP_001008394.1	Q504U0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4orf46	ENST00000508836.1	TSL:1	n.225T>C		non_coding_transcript_exon	Exon 1 of 2
	ETFDH	ENST00000908056.1		c.-284A>G		5_prime_UTR	Exon 1 of 14	ENSP00000578115.1
	ETFDH	ENST00000512251.6	TSL:4	n.64A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1754 AN: 151906 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.00235 AC: 937 AN: 398510 Hom.: 13 Cov.: 3 AF XY: 0.00220 AC XY: 458 AN XY: 207870

African (AFR) AF: 0.0394 AC: 448 AN: 11370

American (AMR) AF: 0.00692 AC: 108 AN: 15596

Ashkenazi Jewish (ASJ) AF: 0.00135 AC: 17 AN: 12580

East Asian (EAS) AF: 0.0000349 AC: 1 AN: 28634

South Asian (SAS) AF: 0.000141 AC: 5 AN: 35480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27854

Middle Eastern (MID) AF: 0.0106 AC: 19 AN: 1786

European-Non Finnish (NFE) AF: 0.000828 AC: 200 AN: 241596

Other (OTH) AF: 0.00589 AC: 139 AN: 23614

GnomAD4 genome AF: 0.0116 AC: 1769 AN: 152024 Hom.: 28 Cov.: 32 AF XY: 0.0113 AC XY: 841 AN XY: 74322

African (AFR) AF: 0.0378 AC: 1568 AN: 41438

American (AMR) AF: 0.00720 AC: 110 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 67960

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.00623 Hom.: 3

Bravo AF: 0.0135

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		-0.31
PromoterAI		-0.024	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs78201564; hg19: chr4-159593183;