rs186739072

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_004260.4(RECQL4):c.2755G>A(p.Ala919Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000822 in 1,605,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A919A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense, splice_region

Scores

Splicing: ADA: 0.7358

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.78

Publications

2 publications found

Variant links:

COSMIC-nc: COSV56742697

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:

ENSG00000265393 (HGNC:):

ENSG00000265393 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 34 uncertain in NM_004260.4

BP4

Computational evidence support a benign effect (MetaRNN=0.026569337).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL4	NM_004260.4	MANE Select	c.2755G>A	p.Ala919Thr	missense splice_region	Exon 15 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.2755G>A	p.Gly919Ser	missense	Exon 15 of 20	NP_001399948.1
RECQL4	NM_001413023.1		c.1684G>A	p.Gly562Ser	missense	Exon 14 of 19	NP_001399952.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2755G>A	p.Ala919Thr	missense splice_region	Exon 15 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.1684G>A	p.Ala562Thr	missense splice_region	Exon 14 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.2662G>A	p.Ala888Thr	missense splice_region	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000223

AC:

AN:

233186

AF XY:

0.000197

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00112

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000764

Gnomad OTH exome

AF:

0.000872

GnomAD4 exome

AF:

0.0000840

AC:

122

AN:

1452704

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

721978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.000964

AC:

AN:

43550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.000381

AC:

AN:

39360

South Asian (SAS)

AF:

0.0000235

AC:

AN:

85060

European-Finnish (FIN)

AF:

0.0000389

AC:

AN:

51440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000523

AC:

AN:

1108232

Other (OTH)

AF:

0.0000499

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41594

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

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:

0.0000647

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000208

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Baller-Gerold syndrome (1)

not provided (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.010

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.034

MetaRNN

Benign

0.027

MutationAssessor

Uncertain

2.1

PhyloP100

3.8

PrimateAI

Benign

0.38

Sift4G

Benign

0.85

Polyphen

0.027

Vest4

0.39

MVP

0.48

GERP RS

5.2

PromoterAI

0.00040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.20

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.74

dbscSNV1_RF

Benign

0.60

SpliceAI score (max)

0.77

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.24

Position offset: -14

DS_DL_spliceai

0.77

Position offset: 0

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