19-29213095-T-C

Variant names:

• chr19-29213095-T-C
• rs11666764
• NM_006003.3:c.24A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006003.3(UQCRFS1):​c.24A>G​(p.Ser8Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.93 in 152,110 control chromosomes in the GnomAD database, including 65,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65752 hom., cov: 37)
  • Exomes 𝑓: 0.92 (579285 hom.)
  • Failed GnomAD Quality Control
• Consequence: UQCRFS1 NM_006003.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.645
• Publications: 15 publications found

Genes affected

UQCRFS1 (HGNC:12587): (ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1) Predicted to enable oxidoreductase activity. Involved in mitochondrial respiratory chain complex III assembly and respiratory electron transport chain. Located in mitochondrion. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. Implicated in mitochondrial complex III deficiency. [provided by Alliance of Genome Resources, Apr 2022]

UQCRFS1-DT (HGNC:55295): (UQCRFS1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-29213095-T-C is Benign according to our data. Variant chr19-29213095-T-C is described in ClinVar as Benign. ClinVar VariationId is 1684191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.645 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006003.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UQCRFS1	NM_006003.3	MANE Select	c.24A>G	p.Ser8Ser	synonymous	Exon 1 of 2	NP_005994.2	P47985
	UQCRFS1-DT	NR_184021.1		n.-158T>C		upstream_gene	N/A
	UQCRFS1-DT	NR_184022.1		n.-158T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UQCRFS1	ENST00000304863.6	TSL:1 MANE Select	c.24A>G	p.Ser8Ser	synonymous	Exon 1 of 2	ENSP00000306397.3	P47985
	UQCRFS1	ENST00000933914.1		c.24A>G	p.Ser8Ser	synonymous	Exon 1 of 2	ENSP00000603973.1
	UQCRFS1-DT	ENST00000587859.2	TSL:2	n.-113T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.930 AC: 141304 AN: 152000 Hom.: 65700 Cov.: 37

Gnomad AFR AF: 0.935

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.910

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.922

GnomAD2 exomes AF: 0.932 AC: 95447 AN: 102368 AF XY: 0.933

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.945

Gnomad ASJ exome AF: 0.907

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.936

Gnomad NFE exome AF: 0.910

Gnomad OTH exome AF: 0.913

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.924 AC: 1252892 AN: 1355800 Hom.: 579285 Cov.: 51 AF XY: 0.925 AC XY: 618591 AN XY: 669030

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

African (AFR) AF: 0.935 AC: 26050 AN: 27854

American (AMR) AF: 0.942 AC: 31182 AN: 33090

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 21910 AN: 24066

East Asian (EAS) AF: 1.00 AC: 31755 AN: 31764

South Asian (SAS) AF: 0.955 AC: 74150 AN: 77648

European-Finnish (FIN) AF: 0.931 AC: 30918 AN: 33202

Middle Eastern (MID) AF: 0.897 AC: 4139 AN: 4614

European-Non Finnish (NFE) AF: 0.919 AC: 980441 AN: 1066974

Other (OTH) AF: 0.925 AC: 52347 AN: 56588

⚠️ 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.

GnomAD4 genome AF: 0.930 AC: 141411 AN: 152110 Hom.: 65752 Cov.: 37 AF XY: 0.931 AC XY: 69251 AN XY: 74354

African (AFR) AF: 0.935 AC: 38811 AN: 41528

American (AMR) AF: 0.929 AC: 14205 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.910 AC: 3158 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5149 AN: 5154

South Asian (SAS) AF: 0.966 AC: 4672 AN: 4834

European-Finnish (FIN) AF: 0.939 AC: 9949 AN: 10596

Middle Eastern (MID) AF: 0.921 AC: 269 AN: 292

European-Non Finnish (NFE) AF: 0.919 AC: 62435 AN: 67916

Other (OTH) AF: 0.924 AC: 1950 AN: 2110

Alfa AF: 0.913 Hom.: 5897

Bravo AF: 0.928

Asia WGS AF: 0.981 AC: 3413 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial complex III deficiency, nuclear type 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.8
DANN	Benign	0.46
PhyloP100		-0.65
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11666764; hg19: chr19-29704002; COSMIC: COSV59184859; COSMIC: COSV59184859;