Genetic Variant RECQL4:p.Leu1043Leu (chr8-144512253-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001413019.1(RECQL4):c.3202T>C(p.Leu1068Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,612,502 control chromosomes in the GnomAD database, including 789,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1068L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.99 ( 74151 hom., cov: 37)

Exomes 𝑓: 0.99 ( 715666 hom. )

Consequence

RECQL4
NM_001413019.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.01

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

Baller-Gerold syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

RECQL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 8-144512253-A-G is Benign according to our data. Variant chr8-144512253-A-G is described in ClinVar as Benign. ClinVar VariationId is 167573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413019.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RECQL4	NM_004260.4	MANE Select	c.3127T>C	p.Leu1043Leu	synonymous	Exon 18 of 21	NP_004251.4
RECQL4	NM_001413019.1		c.3202T>C	p.Leu1068Leu	synonymous	Exon 17 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.3127T>C	p.Leu1043Leu	synonymous	Exon 18 of 21	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3127T>C	p.Leu1043Leu	synonymous	Exon 18 of 21	ENSP00000482313.2
RECQL4	ENST00000621189.4	TSL:1	c.2056T>C	p.Leu686Leu	synonymous	Exon 17 of 20	ENSP00000483145.1
RECQL4	ENST00000971710.1		c.3034T>C	p.Leu1012Leu	synonymous	Exon 18 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.986

AC:

150063

AN:

152226

Hom.:

74094

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.952

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.788

Gnomad SAS

AF:

0.997

Gnomad FIN

AF:

0.998

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.989

GnomAD2 exomes

AF:

0.970

AC:

239773

AN:

247306

AF XY:

0.975

show subpopulations

Gnomad AFR exome

AF:

0.995

Gnomad AMR exome

AF:

0.904

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

0.786

Gnomad FIN exome

AF:

0.997

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.981

GnomAD4 exome

AF:

0.989

AC:

1443943

AN:

1460158

Hom.:

715666

Cov.:

AF XY:

0.990

AC XY:

718755

AN XY:

726346

show subpopulations

African (AFR)

AF:

0.996

AC:

33344

AN:

33478

American (AMR)

AF:

0.909

AC:

40639

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26131

AN:

26132

East Asian (EAS)

AF:

0.732

AC:

29071

AN:

39690

South Asian (SAS)

AF:

0.998

AC:

86125

AN:

86258

European-Finnish (FIN)

AF:

0.996

AC:

51827

AN:

52016

Middle Eastern (MID)

AF:

0.997

AC:

5748

AN:

5766

European-Non Finnish (NFE)

AF:

1.00

AC:

1111418

AN:

1111762

Other (OTH)

AF:

0.988

AC:

59640

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

936

1872

2807

3743

4679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21648

43296

64944

86592

108240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.986

AC:

150179

AN:

152344

Hom.:

74151

Cov.:

AF XY:

0.984

AC XY:

73312

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.994

AC:

41342

AN:

41584

American (AMR)

AF:

0.952

AC:

14581

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

0.787

AC:

4066

AN:

5164

South Asian (SAS)

AF:

0.997

AC:

4816

AN:

4830

European-Finnish (FIN)

AF:

0.998

AC:

10604

AN:

10628

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68000

AN:

68034

Other (OTH)

AF:

0.989

AC:

2092

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

103

207

310

414

517

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.989

Hom.:

195802

Bravo

AF:

0.981

Asia WGS

AF:

0.939

AC:

3266

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Baller-Gerold syndrome (2)

not provided (1)

not specified (1)

Rapadilino syndrome (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.9

(source)

DANN

Benign

0.66

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over