rs35407712

chr8-144514992-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):c.1564C>T(p.Arg522Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,611,370 control chromosomes in the GnomAD database, including 333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (61 hom., cov: 34)
  • Exomes 𝑓: 0.0035 (272 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.50

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 -18 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, 14 uncertain in NM_004260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029628873).
• BP6: Variant 8-144514992-G-A is Benign according to our data. Variant chr8-144514992-G-A is described in ClinVar as [Benign]. Clinvar id is 135173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514992-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1564C>T	p.Arg522Cys	missense_variant	9/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1564C>T	p.Arg522Cys	missense_variant	9/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.493C>T	p.Arg165Cys	missense_variant	8/20	1
RECQL4	ENST00000532846.2	c.421C>T	p.Arg141Cys	missense_variant	5/9	5
RECQL4	ENST00000688394.1	n.587C>T		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1340 AN: 152156 Hom.: 61 Cov.: 34

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.0168 AC: 4090 AN: 243556 Hom.: 224 AF XY: 0.0122 AC XY: 1620 AN XY: 133096

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000455

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.00352 AC: 5142 AN: 1459096 Hom.: 272 Cov.: 33 AF XY: 0.00284 AC XY: 2059 AN XY: 725724

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000684

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00881 AC: 1342 AN: 152274 Hom.: 61 Cov.: 34 AF XY: 0.0105 AC XY: 782 AN XY: 74462

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00102 Hom.: 6

Bravo AF: 0.0149

ESP6500AA AF: 0.000934 AC: 4

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.0115 AC: 1382

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Nov 17, 2015	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 19, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

This variant is associated with the following publications: (PMID: 12734318) -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Benign	0.80
DEOGEN2	Benign	0.11	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0030	T;T
PrimateAI	Benign	0.43	T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.25
GERP RS		5.5
Varity_R		0.25
gMVP		0.60

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: rs35407712; hg19: chr8-145740376; COSMIC: COSV99468414; COSMIC: COSV99468414;