dbSNP rs35876881: RECQL4:c.1704+9C>T (chr8-144514433-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004260.4(RECQL4):c.1704+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,610,918 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

RECQL4
NM_004260.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.123

Publications

4 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, SUPPORTIVE Submitted by: Orphanet, G2P
Rothmund-Thomson syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Rothmund-Thomson syndrome type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
osteosarcoma
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
rapadilino syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RECQL4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 8-144514433-G-A is Benign according to our data. Variant chr8-144514433-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00343 (523/152320) while in subpopulation AFR AF = 0.00633 (263/41564). AF 95% confidence interval is 0.0057. There are 1 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RECQL4	NM_004260.4	MANE Select	c.1704+9C>T	intron	N/A	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.1704+9C>T	intron	N/A	NP_001399948.1
RECQL4	NM_001413036.1		c.1704+9C>T	intron	N/A	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.1704+9C>T	intron	N/A	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.633+9C>T	intron	N/A	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.1611+9C>T	intron	N/A	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.00342

AC:

520

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00908

GnomAD2 exomes

AF:

0.00205

AC:

504

AN:

245540

AF XY:

0.00203

show subpopulations

Gnomad AFR exome

AF:

0.00588

Gnomad AMR exome

AF:

0.00356

Gnomad ASJ exome

AF:

0.00560

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00195

Gnomad OTH exome

AF:

0.00285

GnomAD4 exome

AF:

0.00245

AC:

3569

AN:

1458598

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1715

AN XY:

725370

show subpopulations

African (AFR)

AF:

0.00616

AC:

206

AN:

33446

American (AMR)

AF:

0.00379

AC:

169

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.00611

AC:

159

AN:

26020

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000151

AC:

AN:

86072

European-Finnish (FIN)

AF:

0.000192

AC:

AN:

52086

Middle Eastern (MID)

AF:

0.00278

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00254

AC:

2821

AN:

1110738

Other (OTH)

AF:

0.00290

AC:

175

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

180

360

540

720

900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00343

AC:

523

AN:

152320

Hom.:

Cov.:

AF XY:

0.00329

AC XY:

245

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00633

AC:

263

AN:

41564

American (AMR)

AF:

0.00438

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00219

AC:

149

AN:

68024

Other (OTH)

AF:

0.00899

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00290

Hom.:

Bravo

AF:

0.00407

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Baller-Gerold syndrome (2)

not specified (2)

Hereditary cancer-predisposing syndrome (1)

Rapadilino syndrome (1)

RECQL4-related disorder (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

0.12

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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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