19-29207997-C-A

Variant names:

• chr19-29207997-C-A
• rs146164627
• NM_006003.3:c.376G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006003.3(UQCRFS1):​c.376G>T​(p.Ala126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UQCRFS1 NM_006003.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75
• Publications: 0 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 Gene-Disease associations (from GenCC):

• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex III deficiency, nuclear type 10

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.376G>T	p.Ala126Ser	missense	Exon 2 of 2	NP_005994.2	P47985

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UQCRFS1	ENST00000304863.6	TSL:1 MANE Select	c.376G>T	p.Ala126Ser	missense	Exon 2 of 2	ENSP00000306397.3	P47985
	UQCRFS1	ENST00000933914.1		c.346G>T	p.Ala116Ser	missense	Exon 2 of 2	ENSP00000603973.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.7
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.24	B
Vest4		0.40
MutPred		0.72		Gain of loop (P = 0.0195)
MVP		0.55
MPC		1.5
ClinPred		0.48	T
GERP RS		2.1
Varity_R		0.16
gMVP		0.78
Mutation Taster		=80/20	polymorphism

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: rs146164627; hg19: chr19-29698904;