4-158672031-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000508836.1(C4orf46):n.225T>C 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 0.00492 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: C4orf46 ENST00000508836.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.310

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 -14 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 id is 1212006.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4orf46	NR_077234.2	n.26T>C		non_coding_transcript_exon_variant	1/2
C4orf46	NR_077235.2	n.26T>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4orf46	ENST00000508836.1	n.225T>C		non_coding_transcript_exon_variant	1/2	1
ETFDH	ENST00000512251.6	n.64A>G		non_coding_transcript_exon_variant	1/2	4

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

Gnomad4 AFR exome AF: 0.0394

Gnomad4 AMR exome AF: 0.00692

Gnomad4 ASJ exome AF: 0.00135

Gnomad4 EAS exome AF: 0.0000349

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000828

Gnomad4 OTH exome AF: 0.00589

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

Gnomad4 AFR AF: 0.0378

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.00569 Hom.: 1

Bravo AF: 0.0135

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.6
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs78201564; hg19: chr4-159593183;