8-144513445-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004260.4(RECQL4):​c.2236G>A​(p.Ala746Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,609,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A746A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RECQL4
NM_004260.4 missense

Scores

3
6
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RECQL4NM_004260.4 linkuse as main transcriptc.2236G>A p.Ala746Thr missense_variant 14/21 ENST00000617875.6 NP_004251.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RECQL4ENST00000617875.6 linkuse as main transcriptc.2236G>A p.Ala746Thr missense_variant 14/211 NM_004260.4 ENSP00000482313 P1
RECQL4ENST00000621189.4 linkuse as main transcriptc.1165G>A p.Ala389Thr missense_variant 13/201 ENSP00000483145
ENST00000580385.1 linkuse as main transcriptn.272-161C>T intron_variant, non_coding_transcript_variant 3
RECQL4ENST00000534626.6 linkuse as main transcriptc.607G>A p.Ala203Thr missense_variant 5/85 ENSP00000477457

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000536
AC:
13
AN:
242540
Hom.:
0
AF XY:
0.0000677
AC XY:
9
AN XY:
132998
show subpopulations
Gnomad AFR exome
AF:
0.0000671
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000911
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000398
AC:
58
AN:
1457408
Hom.:
0
Cov.:
46
AF XY:
0.0000496
AC XY:
36
AN XY:
725182
show subpopulations
Gnomad4 AFR exome
AF:
0.000508
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000313
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000720
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000261
Hom.:
0
Bravo
AF:
0.000155
ExAC
AF:
0.0000749
AC:
9

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU DresdenNov 03, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 23, 2022In 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:2
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsMay 31, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 12, 2023This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 746 of the RECQL4 protein (p.Ala746Thr). This variant is present in population databases (rs758736784, gnomAD 0.02%). 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: 407043). 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 expected to disrupt RECQL4 protein function with a positive 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
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
26
DANN
Benign
0.72
DEOGEN2
Benign
0.25
T;D
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.77
D;D
PrimateAI
Uncertain
0.69
T
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
.;D
Vest4
0.82
MVP
0.56
GERP RS
5.7
Varity_R
0.53
gMVP
0.67

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

LitVar

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

Other links and lift over

dbSNP: rs758736784; hg19: chr8-145738829; COSMIC: COSV52881524; COSMIC: COSV52881524; API