8-144512847-C-T

Position:

chr8-144512847-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000617875.6(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
ENST00000617875.6 missense, splice_region

Scores

Splicing: ADA: 0.7358

Clinical Significance

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

Conservation

PhyloP100: 3.78

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2755G>A	p.Ala919Thr	missense_variant, splice_region_variant	15/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2755G>A	p.Ala919Thr	missense_variant, splice_region_variant	15/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1684G>A	p.Ala562Thr	missense_variant, splice_region_variant	14/20	1		ENSP00000483145
	ENST00000580385.1 linkuse as main transcript	n.271+10C>T		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6 linkuse as main transcript	c.928G>A	p.Ala310Thr	missense_variant, splice_region_variant	6/8	5		ENSP00000477457

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

GnomAD3 exomes

AF:

0.000223

AC:

AN:

233186

Hom.:

AF XY:

0.000197

AC XY:

AN XY:

127058

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 SAS exome

AF:

0.0000689

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000964

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000381

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.0000389

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ExAC

AF:

0.000208

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2024

Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 30086788, 35725860, 35171259) -

Rothmund-Thomson syndrome type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 21, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 919 of the RECQL4 protein (p.Ala919Thr). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is present in population databases (rs186739072, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer (PMID: 30086788). ClinVar contains an entry for this variant (Variation ID: 459430). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Benign

0.010

T;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.027

T;T

MutationAssessor

Uncertain

2.1

.;M

PrimateAI

Benign

0.38

Sift4G

Benign

0.85

T;T

Polyphen

0.027

.;B

Vest4

0.39

MVP

0.48

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over