8-144514017-C-A

Variant names:

• chr8-144514017-C-A
• rs993147176
• NM_004260.4:c.1969G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.1969G>T​(p.Ala657Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,419,434 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A657V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.89
• Publications: 0 publications found

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, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38025144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1969G>T	p.Ala657Ser	missense_variant	Exon 12 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1969G>T	p.Ala657Ser	missense_variant	Exon 12 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.898G>T	p.Ala300Ser	missense_variant	Exon 11 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.337G>T	p.Ala113Ser	missense_variant	Exon 3 of 8	5		ENSP00000477457.1
RECQL4	ENST00000532846.2	c.823G>T	p.Ala275Ser	missense_variant	Exon 8 of 9	5		ENSP00000476551.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419434 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 702592

African (AFR) AF: 0.00 AC: 0 AN: 32404

American (AMR) AF: 0.00 AC: 0 AN: 38596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25408

East Asian (EAS) AF: 0.00 AC: 0 AN: 37082

South Asian (SAS) AF: 0.00 AC: 0 AN: 81148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5636

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1091470

Other (OTH) AF: 0.00 AC: 0 AN: 58822

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A657S variant (also known as c.1969G>T), located in coding exon 12 of the RECQL4 gene, results from a G to T substitution at nucleotide position 1969. The alanine at codon 657 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Baller-Gerold syndrome Uncertain:1

Feb 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 657 of the RECQL4 protein (p.Ala657Ser). This variant is not present in population databases (gnomAD no frequency). 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: 837409). 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. -

Baller-Gerold syndrome;C1849453:Rapadilino syndrome Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.0035	T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.38	T;T
PhyloP100		5.9
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.17	T;T
Polyphen		0.057	.;B
Vest4		0.40
MVP		0.62
GERP RS		5.4
PromoterAI		-0.024	Neutral
Varity_R		0.23
gMVP		0.35
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs993147176; hg19: chr8-145739401;