rs754735053

Variant names:

• chr8-144514988-C-G
• rs754735053
• NM_004260.4:c.1568G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144514988-C-G
• chr8-144514988-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_004260.4(RECQL4):​c.1568G>C​(p.Ser523Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,611,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S523G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00041 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 3.00
• Publications: 9 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 32 uncertain in NM_004260.4
• BP6: Variant 8-144514988-C-G is Benign according to our data. Variant chr8-144514988-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 259258.

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.1568G>C	p.Ser523Thr	missense	Exon 9 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1568G>C	p.Ser523Thr	missense	Exon 9 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1568G>C	p.Ser523Thr	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.1568G>C	p.Ser523Thr	missense	Exon 9 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.497G>C	p.Ser166Thr	missense	Exon 8 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1475G>C	p.Ser492Thr	missense	Exon 9 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152186 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000246 AC: 60 AN: 244018 AF XY: 0.000240

Gnomad AFR exome AF: 0.0000675

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000427

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000410 AC: 599 AN: 1459330 Hom.: 0 Cov.: 33 AF XY: 0.000405 AC XY: 294 AN XY: 725822

African (AFR) AF: 0.0000897 AC: 3 AN: 33462

American (AMR) AF: 0.000202 AC: 9 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

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

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86098

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51978

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.000496 AC: 551 AN: 1111500

Other (OTH) AF: 0.000332 AC: 20 AN: 60278

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152304 Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 25 AN XY: 74484

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000915 AC: 14 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68004

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000506

ExAC AF: 0.000232 AC: 28

EpiCase AF: 0.000436

EpiControl AF: 0.000655

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Baller-Gerold syndrome (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	1	-	Rothmund-Thomson syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.75
DEOGEN2	Benign	0.032	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0069	T
MetaRNN	Uncertain	0.47	T
PhyloP100		3.0
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.096	T
Polyphen		0.64	P
Vest4		0.81
MVP		0.79
GERP RS		4.6
PromoterAI		0.024	Neutral
Varity_R		0.22
gMVP		0.56
Mutation Taster		=88/12	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: rs754735053; hg19: chr8-145740372; COSMIC: COSV104618514; COSMIC: COSV104618514;