rs774274636

Positions:

• chr8-144512747-A-C
• chr8-144512747-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_004260.4(RECQL4):​c.2780T>G​(p.Leu927Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.84

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 8-144512747-A-C is Pathogenic according to our data. Variant chr8-144512747-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 863644.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.2780T>G	p.Leu927Arg	missense_variant	16/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.2780T>G	p.Leu927Arg	missense_variant	16/21	1	NM_004260.4	ENSP00000482313	P1
	ENST00000580385.1	n.181A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000122 AC: 3 AN: 246440 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134430

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459752 Hom.: 0 Cov.: 66 AF XY: 0.00000551 AC XY: 4 AN XY: 726170

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000756

ExAC AF: 0.0000166 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Dec 15, 2020

- -

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

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. 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 expected to disrupt RECQL4 protein function. ClinVar contains an entry for this variant (Variation ID: 863644). This variant is also known as g.T5007G, p.L926R. This missense change has been observed in individual(s) with clinical features of Rothmund-Thomson syndrome (PMID: 18616953, 34308366). This variant is present in population databases (rs774274636, gnomAD 0.003%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 927 of the RECQL4 protein (p.Leu927Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Benign	0.80
DEOGEN2	Benign	0.35	T;D;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.78	D;D;D
MutationAssessor	Pathogenic	3.2	.;M;.
PrimateAI	Uncertain	0.63	T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.89
MVP		0.47
GERP RS		5.3
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Varity_R		0.65
gMVP		0.76

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: rs774274636; hg19: chr8-145738130;