Genetic Variant NM_004260.4:c.37G>T (chr8-144517748-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004260.4(RECQL4):c.37G>T(p.Ala13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000977 in 1,330,508 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A13P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000093 ( 1 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.393

Publications

0 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 links:

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

LRRC14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04232186).

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.37G>T	p.Ala13Ser	missense	Exon 1 of 21	NP_004251.4	O94761
RECQL4	NM_001413019.1		c.37G>T	p.Ala13Ser	missense	Exon 1 of 20	NP_001399948.1
RECQL4	NM_001413036.1		c.37G>T	p.Ala13Ser	missense	Exon 1 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.37G>T	p.Ala13Ser	missense	Exon 1 of 21	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4	TSL:1	c.-1100G>T		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1	A0A087X072
RECQL4	ENST00000971710.1		c.37G>T	p.Ala13Ser	missense	Exon 1 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000741

AC:

AN:

40478

AF XY:

0.000123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000933

AC:

AN:

1179572

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

575368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23516

American (AMR)

AF:

0.00

AC:

AN:

16048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17888

East Asian (EAS)

AF:

0.00

AC:

AN:

25096

South Asian (SAS)

AF:

0.000205

AC:

AN:

48694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26818

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3282

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

971022

Other (OTH)

AF:

0.00

AC:

AN:

47208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0000133

AC:

AN:

150936

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41304

American (AMR)

AF:

0.00

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000413

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67592

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

ExAC

AF:

0.000333

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)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.6

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.029

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.48

M_CAP

Benign

0.048

MetaRNN

Benign

0.042

PhyloP100

0.39

PrimateAI

Pathogenic

0.82

Sift4G

Benign

0.61

Polyphen

0.45

Vest4

0.060

MVP

0.66

GERP RS

2.5

PromoterAI

0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.071

gMVP

0.088

Mutation Taster

=98/2

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