rs35842750

Variant names:

• chr8-144514991-C-T
• rs35842750
• NM_004260.4:c.1565G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-144514991-C-T
• chr8-144514991-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):​c.1565G>A​(p.Arg522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,611,498 control chromosomes in the GnomAD database, including 202 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R522C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.019 (90 hom., cov: 34)
  • Exomes 𝑓: 0.0030 (112 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.01
• Publications: 11 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 31 uncertain in NM_004260.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043632984).
• BP6: Variant 8-144514991-C-T is Benign according to our data. Variant chr8-144514991-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 135176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 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.1565G>A	p.Arg522His	missense	Exon 9 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1565G>A	p.Arg522His	missense	Exon 9 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1565G>A	p.Arg522His	missense	Exon 9 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.1565G>A	p.Arg522His	missense	Exon 9 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.494G>A	p.Arg165His	missense	Exon 8 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1472G>A	p.Arg491His	missense	Exon 9 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2942 AN: 152090 Hom.: 90 Cov.: 34

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.0392

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00650 AC: 1586 AN: 243834 AF XY: 0.00542

Gnomad AFR exome AF: 0.0654

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.0365

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000334

Gnomad NFE exome AF: 0.000737

Gnomad OTH exome AF: 0.00454

GnomAD4 exome AF: 0.00298 AC: 4348 AN: 1459290 Hom.: 112 Cov.: 33 AF XY: 0.00274 AC XY: 1986 AN XY: 725830

African (AFR) AF: 0.0696 AC: 2328 AN: 33456

American (AMR) AF: 0.00455 AC: 203 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 953 AN: 26088

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

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86098

European-Finnish (FIN) AF: 0.000289 AC: 15 AN: 51964

Middle Eastern (MID) AF: 0.00529 AC: 30 AN: 5670

European-Non Finnish (NFE) AF: 0.000350 AC: 389 AN: 1111506

Other (OTH) AF: 0.00629 AC: 379 AN: 60254

GnomAD4 genome AF: 0.0194 AC: 2955 AN: 152208 Hom.: 90 Cov.: 34 AF XY: 0.0190 AC XY: 1413 AN XY: 74414

African (AFR) AF: 0.0640 AC: 2658 AN: 41512

American (AMR) AF: 0.00562 AC: 86 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0392 AC: 136 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67988

Other (OTH) AF: 0.0137 AC: 29 AN: 2110

Alfa AF: 0.0124 Hom.: 19

Bravo AF: 0.0219

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0674 AC: 289

ESP6500EA AF: 0.00247 AC: 21

ExAC AF: 0.00696 AC: 839

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000774

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (3)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Rapadilino syndrome (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.060	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0044	T
PhyloP100		2.0
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.10	T
Polyphen		0.96	D
Vest4		0.47
MVP		0.75
GERP RS		5.5
PromoterAI		-0.00040	Neutral
Varity_R		0.18
gMVP		0.54
Mutation Taster		=62/38	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: rs35842750; hg19: chr8-145740375; COSMIC: COSV52880944; COSMIC: COSV52880944;