12-21470214-T-C

Variant summary

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

The NM_002907.4(RECQL):c.1930A>G(p.Arg644Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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. R644I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RECQL NM_002907.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.982

Genes affected

RECQL (HGNC:9948): (RecQ like helicase) The protein encoded by this gene is a member of the RecQ DNA helicase family. DNA helicases are enzymes involved in various types of DNA repair, including mismatch repair, nucleotide excision repair and direct repair. The encoded protein is involved in the processing of Holliday junctions, the suppression of sister chromatid exchanges, telomere maintenance, and is required for genotoxic stress resistance. Defects in this gene have been associated with several types of cancer. [provided by RefSeq, Jan 2017]

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

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=0.14415184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL	NM_002907.4	c.1930A>G	p.Arg644Gly	missense_variant	15/15	ENST00000444129.7
PYROXD1	NM_024854.5	c.*1460T>C		3_prime_UTR_variant	12/12	ENST00000240651.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL	ENST00000444129.7	c.1930A>G	p.Arg644Gly	missense_variant	15/15	2	NM_002907.4	P1
RECQL	ENST00000421138.6	c.1930A>G	p.Arg644Gly	missense_variant	16/16	1		P1
PYROXD1	ENST00000240651.14	c.*1460T>C		3_prime_UTR_variant	12/12	1	NM_024854.5	P1
PYROXD1	ENST00000538582.5	c.*1460T>C		3_prime_UTR_variant	12/12	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 29

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

Invitae

Jan 20, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RECQL-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 644 of the RECQL protein (p.Arg644Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.18
Sift	Benign	0.085	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.063	B;B
Vest4		0.39
MutPred		0.23		Loss of MoRF binding (P = 0.0194);Loss of MoRF binding (P = 0.0194);
MVP		0.70
MPC		2.4
ClinPred		0.47	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.083

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: rs1942902148; hg19: chr12-21623148;