NM_004260.4:c.274T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004260.4(RECQL4):c.274T>C(p.Ser92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,612,104 control chromosomes in the GnomAD database, including 789,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict 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. S92F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.98 ( 73726 hom., cov: 38)

Exomes 𝑓: 0.99 ( 715703 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.157

Publications

44 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 (MetaRNN=8.1035216E-7).

BP6

Variant 8-144517130-A-G is Benign according to our data. Variant chr8-144517130-A-G is described in ClinVar as Benign. ClinVar VariationId is 135161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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_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.274T>C	p.Ser92Pro	missense	Exon 4 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.274T>C	p.Ser92Pro	missense	Exon 4 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.274T>C	p.Ser92Pro	missense	Exon 4 of 21	NP_001399965.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.274T>C	p.Ser92Pro	missense	Exon 4 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.-798T>C		5_prime_UTR	Exon 3 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.274T>C	p.Ser92Pro	missense	Exon 4 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.983

AC:

149666

AN:

152260

Hom.:

73665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.983

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.949

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.804

Gnomad SAS

AF:

0.997

Gnomad FIN

AF:

0.998

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.986

GnomAD2 exomes

AF:

0.970

AC:

237760

AN:

245198

AF XY:

0.975

show subpopulations

Gnomad AFR exome

AF:

0.982

Gnomad AMR exome

AF:

0.902

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

0.803

Gnomad FIN exome

AF:

0.997

Gnomad NFE exome

AF:

0.999

Gnomad OTH exome

AF:

0.981

GnomAD4 exome

AF:

0.989

AC:

1444084

AN:

1459726

Hom.:

715703

Cov.:

AF XY:

0.990

AC XY:

718854

AN XY:

726162

show subpopulations

African (AFR)

AF:

0.984

AC:

32956

AN:

33476

American (AMR)

AF:

0.908

AC:

40490

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26099

AN:

26100

East Asian (EAS)

AF:

0.758

AC:

30071

AN:

39678

South Asian (SAS)

AF:

0.999

AC:

86080

AN:

86208

European-Finnish (FIN)

AF:

0.996

AC:

51704

AN:

51894

Middle Eastern (MID)

AF:

0.996

AC:

5735

AN:

5758

European-Non Finnish (NFE)

AF:

1.00

AC:

1111310

AN:

1111686

Other (OTH)

AF:

0.989

AC:

59639

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

795

1590

2384

3179

3974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<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:

0.983

AC:

149786

AN:

152378

Hom.:

73726

Cov.:

AF XY:

0.982

AC XY:

73148

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.983

AC:

40899

AN:

41596

American (AMR)

AF:

0.949

AC:

14536

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

0.804

AC:

4158

AN:

5174

South Asian (SAS)

AF:

0.997

AC:

4819

AN:

4834

European-Finnish (FIN)

AF:

0.998

AC:

10608

AN:

10632

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68002

AN:

68036

Other (OTH)

AF:

0.986

AC:

2086

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

129

259

388

518

647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.991

Hom.:

111420

Bravo

AF:

0.978

TwinsUK

AF:

1.00

AC:

3707

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.986

AC:

3869

ESP6500EA

AF:

0.999

AC:

8276

ExAC

AF:

0.973

AC:

116620

Asia WGS

AF:

0.945

AC:

3285

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

ClinVar submissions

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 (2)

Rapadilino syndrome (1)

Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.5

(source)

DANN

Benign

0.45

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.13

MetaRNN

Benign

8.1e-7

PhyloP100

0.16

PrimateAI

Benign

0.34

Sift4G

Benign

0.39

Vest4

0.041

GERP RS

2.0

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.14

Mutation Taster

=95/5

polymorphism (auto)

(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