dbSNP rs369119794: UQCRQ:c.-16C>A (chr5-132866685-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014402.5(UQCRQ):c.-16C>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 502,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000020 ( 0 hom. )

Consequence

UQCRQ
NM_014402.5 splice_region

Scores

Splicing: ADA: 0.00002832

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.714

Publications

0 publications found

Variant links:

Genes affected

UQCRQ (HGNC:29594): (ubiquinol-cytochrome c reductase complex III subunit VII) This gene encodes a ubiquinone-binding protein of low molecular mass. This protein is a small core-associated protein and a subunit of ubiquinol-cytochrome c reductase complex III, which is part of the mitochondrial respiratory chain. [provided by RefSeq, Jul 2008]

UQCRQ links:

GDF9 (HGNC:4224): (growth differentiation factor 9) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. This protein regulates ovarian function. Reduced expression of this gene may be associated with polycystic ovary syndrome and mutations in this gene may be more common in mothers of dizygotic twins. [provided by RefSeq, Jul 2016]

GDF9 Gene-Disease associations (from GenCC):

premature ovarian failure 14
Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

GDF9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014402.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UQCRQ	NM_014402.5	MANE Select	c.-16C>A	splice_region	Exon 1 of 3	NP_055217.2	O14949
UQCRQ	NM_014402.5	MANE Select	c.-16C>A	5_prime_UTR	Exon 1 of 3	NP_055217.2	O14949
GDF9	NM_005260.7	MANE Select	c.-2152G>T	upstream_gene	N/A	NP_005251.1	O60383

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UQCRQ	ENST00000378670.8	TSL:1 MANE Select	c.-16C>A	splice_region	Exon 1 of 3	ENSP00000367939.3	O14949
UQCRQ	ENST00000378670.8	TSL:1 MANE Select	c.-16C>A	5_prime_UTR	Exon 1 of 3	ENSP00000367939.3	O14949
UQCRQ	ENST00000378665.1	TSL:1	c.-197C>A	5_prime_UTR	Exon 1 of 2	ENSP00000367934.1	O14949

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000199

AC:

AN:

502700

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

262896

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

13478

American (AMR)

AF:

0.00

AC:

AN:

19698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14126

East Asian (EAS)

AF:

0.0000320

AC:

AN:

31220

South Asian (SAS)

AF:

0.00

AC:

AN:

47840

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2104

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

317012

Other (OTH)

AF:

0.00

AC:

AN:

27808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

2.5

(source)

DANN

Benign

0.63

PhyloP100

-0.71

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.012

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over