rs35198096

chr8-144517466-T-Cchr8-144517466-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):c.161A>G(p.Gln54Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,596,194 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q54H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (12 hom., cov: 35)
  • Exomes 𝑓: 0.0032 (31 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.370

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032030642).
• BP6: Variant 8-144517466-T-C is Benign according to our data. Variant chr8-144517466-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 135157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144517466-T-C is described in Lovd as [Benign]. Variant chr8-144517466-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00973 (1481/152230) while in subpopulation AFR AF= 0.0277 (1151/41542). AF 95% confidence interval is 0.0264. There are 12 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.161A>G	p.Gln54Arg	missense_variant	3/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.161A>G	p.Gln54Arg	missense_variant	3/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00963 AC: 1465 AN: 152116 Hom.: 11 Cov.: 35

Gnomad AFR AF: 0.0274

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00365 AC: 776 AN: 212724 Hom.: 4 AF XY: 0.00334 AC XY: 395 AN XY: 118178

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000528

Gnomad FIN exome AF: 0.000138

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.00478

GnomAD4 exome AF: 0.00325 AC: 4692 AN: 1443964 Hom.: 31 Cov.: 32 AF XY: 0.00308 AC XY: 2208 AN XY: 717566

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00589

Gnomad4 ASJ exome AF: 0.00715

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000461

Gnomad4 FIN exome AF: 0.000202

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00973 AC: 1481 AN: 152230 Hom.: 12 Cov.: 35 AF XY: 0.00940 AC XY: 700 AN XY: 74452

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00352 Hom.: 4

Bravo AF: 0.0111

ESP6500AA AF: 0.0135 AC: 42

ESP6500EA AF: 0.00135 AC: 10

ExAC AF: 0.00347 AC: 405

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 09, 2020

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	1.6
Dann	Benign	0.62
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0032	T
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.054
MVP		0.76
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35198096; hg19: chr8-145742850; COSMIC: COSV104618493; COSMIC: COSV104618493;