11-126269044-G-C

Variant names:

• chr11-126269044-G-C
• rs552937899
• ENST00000692336:c.-163G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000532125(FOXRED1):​c.-163G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 746,570 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: FOXRED1 ENST00000532125 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.23

Genes affected

FOXRED1 (HGNC:26927): (FAD dependent oxidoreductase domain containing 1) This gene encodes a protein that contains a FAD-dependent oxidoreductase domain. The encoded protein is localized to the mitochondria and may function as a chaperone protein required for the function of mitochondrial complex I. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Dec 2010]

SRPRA (HGNC:11307): (SRP receptor subunit alpha) The gene encodes a subunit of the endoplasmic reticulum signal recognition particle receptor that, in conjunction with the signal recognition particle, is involved in the targeting and translocation of signal sequence tagged secretory and membrane proteins across the endoplasmic reticulum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-126269044-G-C is Benign according to our data. Variant chr11-126269044-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 303531.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00233 (355/152392) while in subpopulation AFR AF= 0.00817 (340/41602). AF 95% confidence interval is 0.00746. There are 3 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPRA	NM_003139.4	c.-240C>G		upstream_gene_variant		ENST00000332118.11	NP_003130.2
FOXRED1	NM_017547.4	c.-163G>C		upstream_gene_variant		ENST00000263578.10	NP_060017.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPRA	ENST00000332118.11	c.-240C>G		upstream_gene_variant		1	NM_003139.4	ENSP00000328023.5
FOXRED1	ENST00000263578.10	c.-163G>C		upstream_gene_variant		1	NM_017547.4	ENSP00000263578.5

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152274 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000503 AC: 63 AN: 125152 Hom.: 0 AF XY: 0.000357 AC XY: 24 AN XY: 67308

Gnomad AFR exome AF: 0.00841

Gnomad AMR exome AF: 0.000344

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 160 AN: 594178 Hom.: 0 Cov.: 7 AF XY: 0.000202 AC XY: 64 AN XY: 317510

Gnomad4 AFR exome AF: 0.00732

Gnomad4 AMR exome AF: 0.000478

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000568

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152392 Hom.: 3 Cov.: 33 AF XY: 0.00221 AC XY: 165 AN XY: 74518

Gnomad4 AFR AF: 0.00817

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00268

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Aug 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs552937899; hg19: chr11-126138939;