dbSNP rs13183734: UQCRQ:c.-35C>T (chr5-132866847-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000378665.1(UQCRQ):c.-35C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,610,612 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 29 hom., cov: 33)

Exomes 𝑓: 0.014 ( 227 hom. )

Consequence

UQCRQ
ENST00000378665.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.145

Publications

3 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 5-132866847-C-T is Benign according to our data. Variant chr5-132866847-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1318354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.013 (1975/152368) while in subpopulation AMR AF = 0.0435 (666/15312). AF 95% confidence interval is 0.0408. There are 29 homozygotes in GnomAd4. There are 946 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000378665.1. 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.-13-22C>T	intron	N/A	NP_055217.2	O14949
GDF9	NM_001288824.4		c.-280G>A	upstream_gene	N/A	NP_001275753.1	B4DXG3
GDF9	NM_001288825.4		c.-396G>A	upstream_gene	N/A	NP_001275754.1	B4DXG3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
UQCRQ	ENST00000378665.1	TSL:1	c.-35C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000367934.1	O14949
UQCRQ	ENST00000378665.1	TSL:1	c.-35C>T	5_prime_UTR	Exon 1 of 2	ENSP00000367934.1	O14949
UQCRQ	ENST00000378670.8	TSL:1 MANE Select	c.-13-22C>T	intron	N/A	ENSP00000367939.3	O14949

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1974

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00362

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.0434

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0146

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0133

AC:

3294

AN:

247398

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.0366

Gnomad ASJ exome

AF:

0.0125

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00514

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0144

AC:

21023

AN:

1458244

Hom.:

227

Cov.:

AF XY:

0.0137

AC XY:

9951

AN XY:

725552

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33460

American (AMR)

AF:

0.0402

AC:

1796

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

312

AN:

26114

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.00339

AC:

292

AN:

86188

European-Finnish (FIN)

AF:

0.00472

AC:

239

AN:

50596

Middle Eastern (MID)

AF:

0.00461

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

0.0157

AC:

17498

AN:

1111784

Other (OTH)

AF:

0.0128

AC:

771

AN:

60304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1129

2258

3387

4516

5645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

686

1372

2058

2744

3430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0130

AC:

1975

AN:

152368

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

946

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00361

AC:

150

AN:

41590

American (AMR)

AF:

0.0435

AC:

666

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00556

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0146

AC:

992

AN:

68036

Other (OTH)

AF:

0.0109

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

105

210

314

419

524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.0147

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

7.5

(source)

DANN

Benign

0.80

PhyloP100

-0.14

PromoterAI

-0.0064

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over