8-144514050-G-T

Variant names:

• chr8-144514050-G-T
• rs398124116
• NM_004260.4:c.1936C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):​c.1936C>A​(p.Arg646Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 8/13 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. R646H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.32
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1936C>A	p.Arg646Ser	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.1936C>A	p.Arg646Ser	missense_variant	Exon 12 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.865C>A	p.Arg289Ser	missense_variant	Exon 11 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.304C>A	p.Arg102Ser	missense_variant	Exon 3 of 8	5		ENSP00000477457.1
RECQL4	ENST00000532846.2	c.790C>A	p.Arg264Ser	missense_variant	Exon 8 of 9	5		ENSP00000476551.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430902 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 709276

African (AFR) AF: 0.00 AC: 0 AN: 32756

American (AMR) AF: 0.00 AC: 0 AN: 40130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37760

South Asian (SAS) AF: 0.00 AC: 0 AN: 82432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097842

Other (OTH) AF: 0.00 AC: 0 AN: 59272

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R646S variant (also known as c.1936C>A), located in coding exon 12 of the RECQL4 gene, results from a C to A substitution at nucleotide position 1936. The arginine at codon 646 is replaced by serine, an amino acid with dissimilar 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

Aug 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 646 of the RECQL4 protein (p.Arg646Ser). 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: 969836). 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	0.23
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.82
DEOGEN2	Benign	0.068	T;T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.43	T;T
PhyloP100		3.3
PrimateAI	Benign	0.25	T
Sift4G	Benign	0.74	T;T
Polyphen		0.25	.;B
Vest4		0.46
MVP		0.76
GERP RS		4.5
PromoterAI		0.0071	Neutral
Varity_R		0.31
gMVP		0.53
Mutation Taster		=78/22	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: rs398124116; hg19: chr8-145739434; COSMIC: COSV99466985; COSMIC: COSV99466985;