8-144517703-G-T

Variant names:

• chr8-144517703-G-T
• rs794726912
• NM_004260.4:c.82C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004260.4(RECQL4):​c.82C>A​(p.Gln28Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q28R) 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, splice_region
• Scores: Splicing: ADA: 0.00004690
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.589
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08801943).

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.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 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.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-1055C>A		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1
	RECQL4	ENST00000524998.1	TSL:3	c.-206C>A		upstream_gene	N/A	ENSP00000476579.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1235402 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 606352

African (AFR) AF: 0.00 AC: 0 AN: 24524

American (AMR) AF: 0.00 AC: 0 AN: 17632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20014

East Asian (EAS) AF: 0.00 AC: 0 AN: 26630

South Asian (SAS) AF: 0.00 AC: 0 AN: 59266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3554

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003562

Other (OTH) AF: 0.00 AC: 0 AN: 50184

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1

Dec 11, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine with lysine at codon 28 of the RECQL4 protein (p.Gln28Lys). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and lysine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class 0"). The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.088	T
PhyloP100		0.59
PrimateAI	Pathogenic	0.82	D
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.068
MVP		0.75
GERP RS		1.5
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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: rs794726912; hg19: chr8-145743087;