rs777256889

Positions:

• chr8-144515161-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.1472G>A​(p.Arg491Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,412,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.74

Genes affected

RECQL4 (HGNC:9949): (RecQ like helicase 4) The protein encoded by this gene is a DNA helicase that belongs to the RecQ helicase family. DNA helicases unwind double-stranded DNA into single-stranded DNAs and may modulate chromosome segregation. This gene is predominantly expressed in thymus and testis. Mutations in this gene are associated with Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes. [provided by RefSeq, Jan 2010]

RECQL4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33124954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1472G>A	p.Arg491Gln	missense_variant	8/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1472G>A	p.Arg491Gln	missense_variant	8/21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.401G>A	p.Arg134Gln	missense_variant	7/20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.356G>A	p.Arg119Gln	missense_variant	4/9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.495G>A		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000173 AC: 3 AN: 173252 Hom.: 0 AF XY: 0.0000323 AC XY: 3 AN XY: 92872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1412788 Hom.: 0 Cov.: 33 AF XY: 0.0000143 AC XY: 10 AN XY: 698330

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000848 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2024

The p.R491Q variant (also known as c.1472G>A), located in coding exon 8 of the RECQL4 gene, results from a G to A substitution at nucleotide position 1472. The arginine at codon 491 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Rothmund-Thomson syndrome;C0265308:Baller-Gerold syndrome;C1849453:Rapadilino syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 04, 2023

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 RECQL4 protein function. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 491 of the RECQL4 protein (p.Arg491Gln). This variant is present in population databases (rs777256889, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 406983). 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	0.10
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.090	T;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.33	T;T
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.053	T;D
Polyphen		0.99	.;D
Vest4		0.40
MVP		0.74
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.27
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777256889; hg19: chr8-145740545;