Genetic Variant NM_004260.4:c.738C>T (chr8-144516381-G-A) – 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_004260.4(RECQL4):c.738C>T(p.Ser246Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,609,020 control chromosomes in the GnomAD database, including 154,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11816 hom., cov: 34)

Exomes 𝑓: 0.44 ( 142394 hom. )

Consequence

RECQL4
NM_004260.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.05

Publications

34 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 8-144516381-G-A is Benign according to our data. Variant chr8-144516381-G-A is described in ClinVar as Benign. ClinVar VariationId is 94897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.505 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.738C>T	p.Ser246Ser	synonymous	Exon 5 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.738C>T	p.Ser246Ser	synonymous	Exon 5 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.738C>T	p.Ser246Ser	synonymous	Exon 5 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.738C>T	p.Ser246Ser	synonymous	Exon 5 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.-334C>T		5_prime_UTR	Exon 4 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.738C>T	p.Ser246Ser	synonymous	Exon 5 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.369

AC:

56126

AN:

152024

Hom.:

11812

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.186

Gnomad AMR

AF:

0.468

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.454

Gnomad SAS

AF:

0.522

Gnomad FIN

AF:

0.491

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.442

Gnomad OTH

AF:

0.384

GnomAD2 exomes

AF:

0.444

AC:

107810

AN:

242800

AF XY:

0.447

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.532

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.452

Gnomad FIN exome

AF:

0.481

Gnomad NFE exome

AF:

0.439

Gnomad OTH exome

AF:

0.429

GnomAD4 exome

AF:

0.438

AC:

637528

AN:

1456878

Hom.:

142394

Cov.:

AF XY:

0.440

AC XY:

319175

AN XY:

724690

show subpopulations

African (AFR)

AF:

0.143

AC:

4795

AN:

33472

American (AMR)

AF:

0.519

AC:

23101

AN:

44536

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

9380

AN:

26102

East Asian (EAS)

AF:

0.396

AC:

15717

AN:

39682

South Asian (SAS)

AF:

0.507

AC:

43669

AN:

86154

European-Finnish (FIN)

AF:

0.481

AC:

23829

AN:

49500

Middle Eastern (MID)

AF:

0.292

AC:

1684

AN:

5764

European-Non Finnish (NFE)

AF:

0.441

AC:

490048

AN:

1111354

Other (OTH)

AF:

0.420

AC:

25305

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

23030

46060

69091

92121

115151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14746

29492

44238

58984

73730

<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:

0.369

AC:

56144

AN:

152142

Hom.:

11816

Cov.:

AF XY:

0.377

AC XY:

28017

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.159

AC:

6603

AN:

41536

American (AMR)

AF:

0.469

AC:

7171

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1197

AN:

3470

East Asian (EAS)

AF:

0.453

AC:

2348

AN:

5178

South Asian (SAS)

AF:

0.522

AC:

2515

AN:

4816

European-Finnish (FIN)

AF:

0.491

AC:

5197

AN:

10578

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.442

AC:

30022

AN:

67956

Other (OTH)

AF:

0.383

AC:

810

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1762

3524

5286

7048

8810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.403

Hom.:

3850

Bravo

AF:

0.357

Asia WGS

AF:

0.501

AC:

1742

AN:

3478

EpiCase

AF:

0.434

EpiControl

AF:

0.434

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Baller-Gerold syndrome (2)

not provided (2)

Rapadilino syndrome (2)

Rothmund-Thomson syndrome type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.25

(source)

DANN

Benign

0.68

PhyloP100

-2.0

PromoterAI

0.00080

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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