rs768110067

Variant names:

• chr8-144513080-G-A
• rs768110067
• NM_004260.4:c.2522C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001413019.1(RECQL4):​c.2522C>T​(p.Ala841Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000418 in 1,577,554 control chromosomes in the GnomAD database, with no homozygous occurrence. 9/14 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. A841S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: RECQL4 NM_001413019.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72
• 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, 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

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413019.1. 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.2522C>T	p.Ala841Val	missense	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2522C>T	p.Ala841Val	missense	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2522C>T	p.Ala841Val	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.2522C>T	p.Ala841Val	missense	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1451C>T	p.Ala484Val	missense	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2429C>T	p.Ala810Val	missense	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000476 AC: 1 AN: 210288 AF XY: 0.00

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: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000442 AC: 63 AN: 1425396 Hom.: 0 Cov.: 66 AF XY: 0.0000554 AC XY: 39 AN XY: 704466

African (AFR) AF: 0.00 AC: 0 AN: 32710

American (AMR) AF: 0.00 AC: 0 AN: 41140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38504

South Asian (SAS) AF: 0.00 AC: 0 AN: 82210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.0000559 AC: 61 AN: 1091856

Other (OTH) AF: 0.0000341 AC: 2 AN: 58728

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000835 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.010	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.48	T
MutationAssessor	Benign	0.020	N
PhyloP100		3.7
PrimateAI	Benign	0.40	T
Sift4G	Benign	0.35	T
Polyphen		0.047	B
Vest4		0.49
MVP		0.65
GERP RS		4.0
PromoterAI		0.078	Neutral
Varity_R		0.15
gMVP		0.55
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs768110067; hg19: chr8-145738463;