NM_004260.4:c.2477G>T

Variant names:

• chr8-144513125-C-A
• rs770800467
• NM_004260.4:c.2477G>T

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.2477G>T​(p.Arg826Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,411,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 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. R826Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0370
• Publications: 2 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19067526).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2477G>T	p.Arg826Leu	missense	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2477G>T	p.Arg826Leu	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2477G>T	p.Arg826Leu	missense	Exon 15 of 21	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2477G>T	p.Arg826Leu	missense	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1406G>T	p.Arg469Leu	missense	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2384G>T	p.Arg795Leu	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.0000120 AC: 17 AN: 1411488 Hom.: 0 Cov.: 66 AF XY: 0.0000101 AC XY: 7 AN XY: 695296

African (AFR) AF: 0.00 AC: 0 AN: 32570

American (AMR) AF: 0.00 AC: 0 AN: 41396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23116

East Asian (EAS) AF: 0.00 AC: 0 AN: 38852

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48756

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5550

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1084458

Other (OTH) AF: 0.00 AC: 0 AN: 58196

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.99
DANN	Benign	0.79
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.19	T
MutationAssessor	Benign	0.65	N
PhyloP100		0.037
PrimateAI	Benign	0.20	T
Sift4G	Benign	0.66	T
Polyphen		0.011	B
Vest4		0.22
MVP		0.73
GERP RS		-3.8
PromoterAI		-0.00010	Neutral
Varity_R		0.36
gMVP		0.53
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs770800467; hg19: chr8-145738508;