6-106640861-G-A

Position:

• chr6-106640861-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018292.5(QRSL1):​c.223G>A​(p.Val75Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V75A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: QRSL1 NM_018292.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

QRSL1 (HGNC:21020): (glutaminyl-tRNA amidotransferase subunit QRSL1) Enables glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity. Involved in glutaminyl-tRNAGln biosynthesis via transamidation and mitochondrial translation. Located in mitochondrion. Part of glutamyl-tRNA(Gln) amidotransferase complex. Implicated in combined oxidative phosphorylation deficiency 40. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11882886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QRSL1	NM_018292.5	c.223G>A	p.Val75Ile	missense_variant	3/11	ENST00000369046.8
QRSL1	XM_011535924.3	c.-51G>A		5_prime_UTR_variant	4/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QRSL1	ENST00000369046.8	c.223G>A	p.Val75Ile	missense_variant	3/11	1	NM_018292.5	P1
QRSL1	ENST00000369044.1	c.223G>A	p.Val75Ile	missense_variant	3/7	2
QRSL1	ENST00000467262.1	n.412G>A		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461470 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 75 of the QRSL1 protein (p.Val75Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with QRSL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2110573). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt QRSL1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.36	N;.
MutationTaster	Benign	0.94	D;D
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.049
Sift	Benign	0.59	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.0060	B;.
Vest4		0.19
MutPred		0.34		Gain of ubiquitination at K76 (P = 0.102);Gain of ubiquitination at K76 (P = 0.102);
MVP		0.54
MPC		0.17
ClinPred		0.22	T
GERP RS		-0.97
Varity_R		0.019
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs367555359; hg19: chr6-107088736;