rs367559549

Variant names:

• chr8-144512949-G-A
• rs367559549
• NM_004260.4:c.2653C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004260.4(RECQL4):​c.2653C>T​(p.Leu885Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,574,550 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. L885R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.421
• 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, SUPPORTIVE Submitted by: Orphanet, G2P
• Rothmund-Thomson syndrome

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

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.064121634).

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.2653C>T	p.Leu885Phe	missense	Exon 15 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2653C>T	p.Leu885Phe	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2653C>T	p.Leu885Phe	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.2653C>T	p.Leu885Phe	missense	Exon 15 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1582C>T	p.Leu528Phe	missense	Exon 14 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2560C>T	p.Leu854Phe	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000161 AC: 3 AN: 186892 AF XY: 0.00000992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000380

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 75 AN: 1422298 Hom.: 0 Cov.: 67 AF XY: 0.0000412 AC XY: 29 AN XY: 703972

African (AFR) AF: 0.00 AC: 0 AN: 32644

American (AMR) AF: 0.00 AC: 0 AN: 38838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 37526

South Asian (SAS) AF: 0.00 AC: 0 AN: 81526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000687 AC: 75 AN: 1092388

Other (OTH) AF: 0.00 AC: 0 AN: 58920

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152252 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000253 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	RECQL4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.4
DANN	Benign	0.51
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.064	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.42
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.72	T
Polyphen		0.56	P
Vest4		0.20
MVP		0.15
GERP RS		-0.95
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.20
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs367559549; hg19: chr8-145738332;