NM_004260.4:c.3185G>A

Variant names:

• chr8-144512195-C-T
• rs558058260
• NM_004260.4:c.3185G>A

Variant summary

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

The NM_004260.4(RECQL4):​c.3185G>A​(p.Arg1062Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,611,800 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. R1062W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 36)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.722
• 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, 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.050734043).

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.3185G>A	p.Arg1062Gln	missense	Exon 18 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.3260G>A	p.Arg1087Gln	missense	Exon 17 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3185G>A	p.Arg1062Gln	missense	Exon 18 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.3185G>A	p.Arg1062Gln	missense	Exon 18 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.2114G>A	p.Arg705Gln	missense	Exon 17 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.3092G>A	p.Arg1031Gln	missense	Exon 18 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151990 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000530 AC: 13 AN: 245504 AF XY: 0.0000596

Gnomad AFR exome AF: 0.0000666

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: 0.0000543

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1459688 Hom.: 0 Cov.: 68 AF XY: 0.0000468 AC XY: 34 AN XY: 726112

African (AFR) AF: 0.0000598 AC: 2 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51848

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111648

Other (OTH) AF: 0.0000498 AC: 3 AN: 60292

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152112 Hom.: 0 Cov.: 36 AF XY: 0.000121 AC XY: 9 AN XY: 74342

African (AFR) AF: 0.000289 AC: 12 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5138

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000584 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	not provided (1)
-	1	-	RECQL4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.0054	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.051	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.72
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.94	T
Polyphen		0.27	B
Vest4		0.16
MVP		0.62
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.19
Mutation Taster		=85/15	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: rs558058260; hg19: chr8-145737578; COSMIC: COSV56741833; COSMIC: COSV56741833;