rs1246782381

Variant names:

• chr8-144513703-T-A
• rs1246782381
• NM_004260.4:c.2068A>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144513703-T-A
• chr8-144513703-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_004260.4(RECQL4):​c.2068A>T​(p.Thr690Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000453 in 1,546,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 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. T690M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.982
• 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

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144513702-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 528913.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2068A>T	p.Thr690Ser	missense	Exon 13 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2068A>T	p.Thr690Ser	missense	Exon 13 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2068A>T	p.Thr690Ser	missense	Exon 13 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2068A>T	p.Thr690Ser	missense	Exon 13 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.997A>T	p.Thr333Ser	missense	Exon 12 of 20	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.436A>T	p.Thr146Ser	missense	Exon 4 of 8	ENSP00000477457.1

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1397924 Hom.: 0 Cov.: 47 AF XY: 0.00000725 AC XY: 5 AN XY: 689480

African (AFR) AF: 0.0000317 AC: 1 AN: 31534

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 35742

South Asian (SAS) AF: 0.00 AC: 0 AN: 79266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078904

Other (OTH) AF: 0.0000173 AC: 1 AN: 57954

GnomAD4 genome AF: 0.00000674 AC: 1 AN: 148316 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 72318

African (AFR) AF: 0.00 AC: 0 AN: 39646

American (AMR) AF: 0.00 AC: 0 AN: 14876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67172

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1

Apr 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 690 of the RECQL4 protein (p.Thr690Ser). 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: 459372). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	9.8
DANN	Benign	0.77
DEOGEN2	Benign	0.0032	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.25	T
PhyloP100		0.98
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.81	T
Polyphen		0.0040	B
Vest4		0.20
MVP		0.73
GERP RS		5.0
Varity_R		0.11
gMVP		0.21
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1246782381; hg19: chr8-145739087; COSMIC: COSV52883388; COSMIC: COSV52883388;