rs548804317

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_004260.4(RECQL4):c.2569_2574del(p.Cys857_Thr858del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,574,460 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0015 ( 38 hom. )

Consequence

RECQL4
NM_004260.4 inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.833

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004260.4.

BP6

Variant 8-144513027-TGGTGCA-T is Benign according to our data. Variant chr8-144513027-TGGTGCA-T is described in ClinVar as [Likely_benign]. Clinvar id is 135140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513027-TGGTGCA-T is described in Lovd as [Likely_benign]. Variant chr8-144513027-TGGTGCA-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0024 (365/152314) while in subpopulation AMR AF= 0.015 (229/15306). AF 95% confidence interval is 0.0134. There are 3 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2569_2574del	p.Cys857_Thr858del	inframe_deletion	15/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2569_2574del	p.Cys857_Thr858del	inframe_deletion	15/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1498_1503del	p.Cys500_Thr501del	inframe_deletion	14/20	1		ENSP00000483145
	ENST00000580385.1 linkuse as main transcript	n.271+205_271+210del		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.740_745del	p.Cys248_Thr249del	inframe_deletion	6/8	5		ENSP00000477457

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0121

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00737

AC:

1382

AN:

187612

Hom.:

AF XY:

0.00575

AC XY:

584

AN XY:

101586

show subpopulations

Gnomad AFR exome

AF:

0.000983

Gnomad AMR exome

AF:

0.0410

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0152

Gnomad SAS exome

AF:

0.000797

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000997

Gnomad OTH exome

AF:

0.00403

GnomAD4 exome

AF:

0.00149

AC:

2114

AN:

1422146

Hom.:

AF XY:

0.00136

AC XY:

958

AN XY:

703984

show subpopulations

Gnomad4 AFR exome

AF:

0.000614

Gnomad4 AMR exome

AF:

0.0361

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0124

Gnomad4 SAS exome

AF:

0.000626

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.00141

GnomAD4 genome

AF:

0.00240

AC:

365

AN:

152314

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.0150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0122

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000293

Hom.:

Bravo

AF:

0.00503

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2019	This variant is associated with the following publications: (PMID: 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RECQL4: PM4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 12, 2016	- -

Rothmund-Thomson syndrome type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, 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 BENIGN. 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) 0215 - In-frame insertion/deletion fully contained in a repetitive region that has low conservation (exon 15). (P) 0251 - Variant is heterozygous. (N) 0306 - Variant is present in gnomAD >=0.03 and <0.05 for a recessive condition (1402 heterozygotes, 30 homozygotes). (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. Two Benign reports (ClinVar). (B) 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 -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2021	- -

Baller-Gerold syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over