rs369852601

Variant names:

• chr8-144514521-G-A
• rs369852601
• NM_004260.4:c.1625C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144514521-G-A
• chr8-144514521-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.1625C>T​(p.Ser542Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000807 in 1,611,196 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S542S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (3 hom., cov: 34)
  • Exomes 𝑓: 0.00084 (22 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.78
• Publications: 2 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, 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009870172).
• BP6: Variant 8-144514521-G-A is Benign according to our data. Variant chr8-144514521-G-A is described in ClinVar as Benign. ClinVar VariationId is 135126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000479 (73/152248) while in subpopulation SAS AF = 0.0128 (62/4826). AF 95% confidence interval is 0.0103. There are 3 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1625C>T	p.Ser542Phe	missense	Exon 10 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.1625C>T	p.Ser542Phe	missense	Exon 10 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1625C>T	p.Ser542Phe	missense	Exon 10 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.1625C>T	p.Ser542Phe	missense	Exon 10 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.554C>T	p.Ser185Phe	missense	Exon 9 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.1532C>T	p.Ser511Phe	missense	Exon 10 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152130 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00166 AC: 407 AN: 244764 AF XY: 0.00226

Gnomad AFR exome AF: 0.0000680

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000253

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.000842 AC: 1228 AN: 1458948 Hom.: 22 Cov.: 36 AF XY: 0.00121 AC XY: 881 AN XY: 725634

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.000112 AC: 5 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0112 AC: 963 AN: 86002

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51892

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111254

Other (OTH) AF: 0.00114 AC: 69 AN: 60296

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152248 Hom.: 3 Cov.: 34 AF XY: 0.000672 AC XY: 50 AN XY: 74456

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.000240 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00168 AC: 203

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Rapadilino syndrome (1)
-	-	1	RECQL4-related disorder (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Benign	0.74
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0099	T
PhyloP100		3.8
PrimateAI	Uncertain	0.51	T
Sift4G	Uncertain	0.022	D
Polyphen		0.93	P
Vest4		0.66
MVP		0.73
GERP RS		3.4
PromoterAI		0.033	Neutral
Varity_R		0.16
gMVP		0.56
Mutation Taster		=90/10	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: rs369852601; hg19: chr8-145739905; COSMIC: COSV107348538; COSMIC: COSV107348538;