chr8-144514199-C-T

Position:

• chr8-144514199-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004260.4(RECQL4):​c.1868G>A​(p.Arg623His) variant causes a missense change. The variant allele was found at a frequency of 0.000822 in 1,612,350 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00083 (2 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1 O:1
• Conservation: PhyloP100: 4.61

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23815933).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1868G>A	p.Arg623His	missense_variant	11/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1868G>A	p.Arg623His	missense_variant	11/21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.797G>A	p.Arg266His	missense_variant	10/20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.236G>A	p.Arg79His	missense_variant	2/8	5		ENSP00000477457.1
RECQL4	ENST00000532846.2	c.722G>A	p.Arg241His	missense_variant	7/9	5		ENSP00000476551.1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152132 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000584 AC: 143 AN: 244978 Hom.: 0 AF XY: 0.000539 AC XY: 72 AN XY: 133594

Gnomad AFR exome AF: 0.000197

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000835 AC: 1219 AN: 1460100 Hom.: 2 Cov.: 36 AF XY: 0.000785 AC XY: 570 AN XY: 726346

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000385

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152250 Hom.: 0 Cov.: 34 AF XY: 0.000618 AC XY: 46 AN XY: 74442

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000830 Hom.: 0

Bravo AF: 0.000589

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000836 AC: 7

ExAC AF: 0.000548 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 04, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (165 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Arg623Cys); 7 heterozygotes, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif. Located in the ATP-binding domain (PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. Reported as a VUS and Likely Benign (ClinVar) and as a VUS in cancer patients (PMID: 28767289). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Apr 24, 2024	The RECQL4 c.1868G>A (p.Arg623His) missense change has a maximum subpopulation frequency of 0.1% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with RECQL4-associated conditions. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The RECQL4 p.Arg623His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs201734382), ClinVar (classified as a VUS by Invitae and Fulgent Genetics) and LOVD 3.0 (classified as a VUS). The variant was identified in control databases in 165 of 276288 chromosomes at a frequency of 0.000597 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 129 of 124888 chromosomes (freq: 0.001033), Latino in 15 of 35252 chromosomes (freq: 0.000426), Other in 3 of 7054 chromosomes (freq: 0.000425), European (Finnish) in 8 of 24974 chromosomes (freq: 0.00032), Ashkenazi Jewish in 3 of 10188 chromosomes (freq: 0.000295), African in 3 of 23878 chromosomes (freq: 0.000126), South Asian in 3 of 30568 chromosomes (freq: 0.000098), and East Asian in 1 of 19486 chromosomes (freq: 0.000051). The p.Arg623 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Baller-Gerold syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2021

The c.1868G>A (p.R623H) alteration is located in exon 11 (coding exon 11) of the RECQL4 gene. This alteration results from a G to A substitution at nucleotide position 1868, causing the arginine (R) at amino acid position 623 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration 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

- -

RECQL4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2024

The RECQL4 c.1868G>A variant is predicted to result in the amino acid substitution p.Arg623His. This variant was reported with uncertain significance in study of individuals with breast and/or ovarian cancer (Supplemental Table 8, Bonache et al. 2018. PubMed ID: 30306255) and in a study of individuals with pancreatic ductal adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289; eAppendix 1, Table 2, Hu et al. 2020. PubMed ID: 32659497). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

May 17, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.092	T;T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.24	T;T
PrimateAI	Uncertain	0.60	T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.99	.;D
Vest4		0.71
MVP		0.70
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.28
gMVP		0.70

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: rs201734382; hg19: chr8-145739583;