4-158672218-G-A

Position:

• chr4-158672218-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000508836.1(C4orf46):​n.38C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 612,414 control chromosomes in the GnomAD database, including 45 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 (17 hom.)
• Consequence: C4orf46 ENST00000508836.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.284

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-158672218-G-A is Benign according to our data. Variant chr4-158672218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 347952.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 = 0.0118 (1795/152324) while in subpopulation AFR AF= 0.0384 (1595/41572). AF 95% confidence interval is 0.0368. There are 28 homozygotes in gnomad4. There are 849 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C4orf46	ENST00000508836.1	n.38C>T		non_coding_transcript_exon_variant	1/2	1
ETFDH	ENST00000436096.3	n.13G>A		non_coding_transcript_exon_variant	1/3	3
ETFDH	ENST00000512251.6	n.251G>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1780 AN: 152206 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00236 AC: 1088 AN: 460090 Hom.: 17 Cov.: 4 AF XY: 0.00216 AC XY: 528 AN XY: 244684

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.00556

Gnomad4 ASJ exome AF: 0.00148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000183

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000856

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.0118 AC: 1795 AN: 152324 Hom.: 28 Cov.: 32 AF XY: 0.0114 AC XY: 849 AN XY: 74484

Gnomad4 AFR AF: 0.0384

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00788 Hom.: 1

Bravo AF: 0.0137

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Multiple acyl-CoA dehydrogenase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs113981461; hg19: chr4-159593370;