rs550469990

chr8-144513255-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004260.4(RECQL4):c.2426G>A(p.Gly809Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000187 in 1,590,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G809R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:3
• Conservation: PhyloP100: 4.47

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.036753565).
• BP6: Variant 8-144513255-C-T is Benign according to our data. Variant chr8-144513255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407006.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.2426G>A	p.Gly809Glu	missense_variant	14/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2426G>A	p.Gly809Glu	missense_variant	14/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1355G>A	p.Gly452Glu	missense_variant	13/20	1
	ENST00000580385.1	n.272-351C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.635-117G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000327 AC: 71 AN: 217010 Hom.: 0 AF XY: 0.000397 AC XY: 48 AN XY: 121052

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00342

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000546

GnomAD4 exome AF: 0.000164 AC: 236 AN: 1438238 Hom.: 0 Cov.: 47 AF XY: 0.000169 AC XY: 121 AN XY: 714510

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000544

Gnomad4 ASJ exome AF: 0.00262

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000940

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000640 Hom.: 0

Bravo AF: 0.000737

ExAC AF: 0.000271 AC: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 04, 2021	The RECQL4 c.2426G>A (p.Gly809Glu) missense change is present in gnomAD at a maximum non-founder subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/8-145738638-C-T?dataset=gnomad_r2_1). In silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with RECQL4-associated disorders. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 23, 2022

DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.2426G>A, in exon 14 that results in an amino acid change, p.Gly809Glu. This sequence change does not appear to have been previously described in individuals with RECQL4-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.34% in the Ashkenazi Jewish subpopulation (dbSNP rs550469990). The p.Gly809Glu change affects a highly conserved amino acid residue located in a domain of the RECQL4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly809Glu substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Gly809Glu change remains unknown at this time. Homozygous or compound heterozygous pathogenic variants in RECQL4 have been identified in individuals with Baller-Gerold syndrome [OMIM #218600], which is characterized by craniosynostosis and radial aplasia. Biallelic pathogenic variants in RECQL4 are also associated with two additional overlapping conditions, Rothmund-Thompson syndrome [OMIM #268400] and RAPADILINO syndrome [OMIM #266280]. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2022

The c.2426G>A (p.G809E) alteration is located in exon 14 (coding exon 14) of the RECQL4 gene. This alteration results from a G to A substitution at nucleotide position 2426, causing the glycine (G) at amino acid position 809 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 15, 2021

- -

RECQL4-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	26
Dann	Benign	0.91
DEOGEN2	Benign	0.27	T;D
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.037	T;T
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	.;D
Vest4		0.39
MVP		0.78
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.38
gMVP		0.73

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: rs550469990; hg19: chr8-145738638;