rs202134651

Variant names:

• chr8-144511753-G-A
• rs202134651
• NM_004260.4:c.3430C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144511753-G-A
• chr8-144511753-G-C

Variant summary

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

The NM_004260.4(RECQL4):​c.3430C>T​(p.Arg1144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,612,468 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R1144G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.80
• Publications: 3 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.

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.3430C>T	p.Arg1144Cys	missense	Exon 20 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.3505C>T	p.Arg1169Cys	missense	Exon 19 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3439C>T	p.Arg1147Cys	missense	Exon 20 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.3430C>T	p.Arg1144Cys	missense	Exon 20 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.2359C>T	p.Arg787Cys	missense	Exon 19 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.3337C>T	p.Arg1113Cys	missense	Exon 20 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000724

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000133 AC: 33 AN: 247554 AF XY: 0.000133

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 256 AN: 1460222 Hom.: 1 Cov.: 36 AF XY: 0.000162 AC XY: 118 AN XY: 726392

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.000250 AC: 13 AN: 52020

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111800

Other (OTH) AF: 0.000182 AC: 11 AN: 60346

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152246 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74380

African (AFR) AF: 0.0000724 AC: 3 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

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

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000351 AC: 3

ExAC AF: 0.000199 AC: 24

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	RECQL4-related disorder (1)
-	1	-	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.53	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.8
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.048	D
Polyphen		0.94	P
Vest4		0.74
MVP		0.71
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.58
Mutation Taster		=68/32	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: rs202134651; hg19: chr8-145737136;