rs200732690

Positions:

• chr8-144514980-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_004260.4(RECQL4):​c.1576C>T​(p.Leu526Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,611,946 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.934

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 -14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_004260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.010399044).
• BP6: Variant 8-144514980-G-A is Benign according to our data. Variant chr8-144514980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 135174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1576C>T	p.Leu526Phe	missense_variant	9/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1576C>T	p.Leu526Phe	missense_variant	9/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.505C>T	p.Leu169Phe	missense_variant	8/20	1
RECQL4	ENST00000532846.2	c.433C>T	p.Leu145Phe	missense_variant	5/9	5
RECQL4	ENST00000688394.1	n.599C>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000763 AC: 187 AN: 245232 Hom.: 1 AF XY: 0.000680 AC XY: 91 AN XY: 133874

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.000700

Gnomad ASJ exome AF: 0.00919

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000921

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.000403 AC: 588 AN: 1459628 Hom.: 2 Cov.: 33 AF XY: 0.000424 AC XY: 308 AN XY: 726020

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000806

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000848

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.000389 AC XY: 29 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000589 AC: 5

ExAC AF: 0.000589 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rapadilino syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 08, 2018

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

RECQL4: BP4 -

Rothmund-Thomson syndrome type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jul 22, 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	-0.18	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.075	T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.010	T;T
PrimateAI	Benign	0.47	T
Sift4G	Uncertain	0.056	T;T
Polyphen		0.38	.;B
Vest4		0.28
MVP		0.27
GERP RS		3.5
Varity_R		0.20
gMVP		0.44

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: rs200732690; hg19: chr8-145740364; COSMIC: COSV105873983; COSMIC: COSV105873983;