8-144513117-G-A

Position:

chr8-144513117-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000617875.6(RECQL4):c.2485C>T(p.Arg829Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,558,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R829H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000099 ( 0 hom. )

Consequence

RECQL4
ENST00000617875.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.34

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:

RECQL4 (HGNC:):

RECQL4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37046236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4 linkuse as main transcript	c.2485C>T	p.Arg829Cys	missense_variant	15/21	ENST00000617875.6	NP_004251.4	O94761

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RECQL4	ENST00000617875.6 linkuse as main transcript	c.2485C>T	p.Arg829Cys	missense_variant	15/21	1	NM_004260.4	ENSP00000482313.2	O94761
RECQL4	ENST00000621189.4 linkuse as main transcript	c.1414C>T	p.Arg472Cys	missense_variant	14/20	1		ENSP00000483145.1	A0A087X072
RECQL4	ENST00000534626.6 linkuse as main transcript	c.655C>T	p.Arg219Cys	missense_variant	6/8	5		ENSP00000477457.1	V9GZ64
ENSG00000265393	ENST00000580385.1 linkuse as main transcript	n.271+280G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

150626

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000969

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000244

AC:

AN:

205004

Hom.:

AF XY:

0.0000271

AC XY:

AN XY:

110734

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.0000323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000566

Gnomad NFE exome

AF:

0.0000218

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000994

AC:

AN:

1407800

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

694022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000486

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000253

Gnomad4 FIN exome

AF:

0.0000206

Gnomad4 NFE exome

AF:

0.00000832

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000531

AC:

AN:

150626

Hom.:

Cov.:

AF XY:

0.0000408

AC XY:

AN XY:

73544

show subpopulations

Gnomad4 AFR

AF:

0.000171

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000969

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000604

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

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

May 03, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Baller-Gerold syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 829 of the RECQL4 protein (p.Arg829Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 528995). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RECQL4 protein function with a negative predictive value of 80%. 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

0.11

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Benign

0.82

DEOGEN2

Benign

0.15

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.37

T;T

MutationAssessor

Uncertain

2.8

.;M

PrimateAI

Uncertain

0.57

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

.;D

Vest4

0.43

MVP

0.61

GERP RS

2.3

Varity_R

0.25

gMVP

0.76

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

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