rs112645305

Variant names:

• chr4-158672047-A-G
• rs112645305
• ENST00000508836.1:n.209T>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.-268A>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 0.00484 in 558,560 control chromosomes in the GnomAD database, including 40 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 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (13 hom.)
• Consequence: ETFDH ENST00000908056.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.809
• Publications: 1 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=-0.52).
• BP6: Variant 4-158672047-A-G is Benign according to our data. Variant chr4-158672047-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1194633.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 (1765/152120) while in subpopulation AFR AF = 0.0377 (1564/41500). AF 95% confidence interval is 0.0361. There are 27 homozygotes in GnomAd4. There are 842 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.10T>C		non_coding_transcript_exon	Exon 1 of 2
	C4orf46	NR_077235.2		n.10T>C		non_coding_transcript_exon	Exon 1 of 2
	ETFDH	NM_004453.4	MANE Select	c.-410A>G		upstream_gene	N/A	NP_004444.2	Q16134-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C4orf46	ENST00000508836.1	TSL:1	n.209T>C		non_coding_transcript_exon	Exon 1 of 2
	ETFDH	ENST00000908056.1		c.-268A>G		5_prime_UTR	Exon 1 of 14	ENSP00000578115.1
	ETFDH	ENST00000512251.6	TSL:4	n.80A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1750 AN: 152002 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.00231 AC: 937 AN: 406440 Hom.: 13 Cov.: 2 AF XY: 0.00216 AC XY: 457 AN XY: 211846

African (AFR) AF: 0.0386 AC: 447 AN: 11578

American (AMR) AF: 0.00644 AC: 105 AN: 16298

Ashkenazi Jewish (ASJ) AF: 0.00141 AC: 18 AN: 12810

East Asian (EAS) AF: 0.00 AC: 0 AN: 29150

South Asian (SAS) AF: 0.000136 AC: 5 AN: 36874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28080

Middle Eastern (MID) AF: 0.0104 AC: 19 AN: 1830

European-Non Finnish (NFE) AF: 0.000838 AC: 206 AN: 245776

Other (OTH) AF: 0.00570 AC: 137 AN: 24044

GnomAD4 genome AF: 0.0116 AC: 1765 AN: 152120 Hom.: 27 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74376

African (AFR) AF: 0.0377 AC: 1564 AN: 41500

American (AMR) AF: 0.00719 AC: 110 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 67966

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.00678 Hom.: 2

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	-0.52
CADD	Benign	0.26
DANN	Benign	0.59
PhyloP100		-0.81
PromoterAI		-0.064	Neutral

Splicing

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

Other links and lift over

dbSNP: rs112645305; hg19: chr4-159593199;