rs4251691

Variant names:

• chr8-144512433-C-T
• rs4251691
• NM_004260.4:c.3014G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):​c.3014G>A​(p.Arg1005Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,608,656 control chromosomes in the GnomAD database, including 170,115 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1005W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (12828 hom., cov: 35)
  • Exomes 𝑓: 0.46 (157287 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.622
• Publications: 47 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.8596988E-4).
• BP6: Variant 8-144512433-C-T is Benign according to our data. Variant chr8-144512433-C-T is described in ClinVar as Benign. ClinVar VariationId is 94891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

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.3014G>A	p.Arg1005Gln	missense	Exon 17 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.3089G>A	p.Arg1030Gln	missense	Exon 16 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3014G>A	p.Arg1005Gln	missense	Exon 17 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.3014G>A	p.Arg1005Gln	missense	Exon 17 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1943G>A	p.Arg648Gln	missense	Exon 16 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2921G>A	p.Arg974Gln	missense	Exon 17 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57446 AN: 152076 Hom.: 12822 Cov.: 35

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.465

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.467 AC: 113725 AN: 243454 AF XY: 0.473

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.557

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.441

Gnomad FIN exome AF: 0.495

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.460 AC: 669553 AN: 1456462 Hom.: 157287 Cov.: 80 AF XY: 0.464 AC XY: 335978 AN XY: 723870

African (AFR) AF: 0.110 AC: 3681 AN: 33432

American (AMR) AF: 0.545 AC: 24238 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10466 AN: 26064

East Asian (EAS) AF: 0.399 AC: 15800 AN: 39580

South Asian (SAS) AF: 0.561 AC: 48313 AN: 86130

European-Finnish (FIN) AF: 0.494 AC: 25367 AN: 51398

Middle Eastern (MID) AF: 0.344 AC: 1980 AN: 5758

European-Non Finnish (NFE) AF: 0.463 AC: 513225 AN: 1109448

Other (OTH) AF: 0.440 AC: 26483 AN: 60138

GnomAD4 genome AF: 0.378 AC: 57456 AN: 152194 Hom.: 12828 Cov.: 35 AF XY: 0.385 AC XY: 28681 AN XY: 74416

African (AFR) AF: 0.126 AC: 5248 AN: 41534

American (AMR) AF: 0.504 AC: 7709 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1328 AN: 3472

East Asian (EAS) AF: 0.443 AC: 2287 AN: 5168

South Asian (SAS) AF: 0.581 AC: 2808 AN: 4834

European-Finnish (FIN) AF: 0.498 AC: 5279 AN: 10596

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.465 AC: 31600 AN: 67976

Other (OTH) AF: 0.412 AC: 872 AN: 2114

Alfa AF: 0.408 Hom.: 6383

Bravo AF: 0.364

TwinsUK AF: 0.456 AC: 1689

ALSPAC AF: 0.464 AC: 1789

ESP6500AA AF: 0.128 AC: 543

ESP6500EA AF: 0.448 AC: 3802

ExAC AF: 0.452 AC: 54259

Asia WGS AF: 0.505 AC: 1757 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (5)
-	-	2	Baller-Gerold syndrome (2)
-	-	2	not provided (2)
-	-	2	Rapadilino syndrome (2)
-	-	2	Rothmund-Thomson syndrome type 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.56
DANN	Benign	0.83
DEOGEN2	Benign	0.024	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.00039	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.62
PrimateAI	Benign	0.22	T
Sift4G	Benign	0.29	T
Polyphen		0.035	B
Vest4		0.059
GERP RS		0.28
PromoterAI		0.017	Neutral
Varity_R		0.063
gMVP		0.60
Mutation Taster		=96/4	polymorphism (auto)

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: rs4251691; hg19: chr8-145737816; COSMIC: COSV56739530; COSMIC: COSV56739530;