8-144515235-C-T

Variant names:

• chr8-144515235-C-T
• rs145615931
• NM_004260.4:c.1398G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004260.4(RECQL4):​c.1398G>A​(p.Pro466Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,588,058 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P466P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00081 (5 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -5.87
• 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, 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 8-144515235-C-T is Benign according to our data. Variant chr8-144515235-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.87 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.1398G>A	p.Pro466Pro	synonymous	Exon 8 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1398G>A	p.Pro466Pro	synonymous	Exon 8 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1398G>A	p.Pro466Pro	synonymous	Exon 8 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.1398G>A	p.Pro466Pro	synonymous	Exon 8 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.327G>A	p.Pro109Pro	synonymous	Exon 7 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1305G>A	p.Pro435Pro	synonymous	Exon 8 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152214 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00611

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00120 AC: 251 AN: 208844 AF XY: 0.00134

Gnomad AFR exome AF: 0.0000837

Gnomad AMR exome AF: 0.000200

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000875

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.000860

Gnomad OTH exome AF: 0.000939

GnomAD4 exome AF: 0.000812 AC: 1166 AN: 1435726 Hom.: 5 Cov.: 33 AF XY: 0.000881 AC XY: 627 AN XY: 712078

African (AFR) AF: 0.0000610 AC: 2 AN: 32806

American (AMR) AF: 0.000222 AC: 9 AN: 40612

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25652

East Asian (EAS) AF: 0.000550 AC: 21 AN: 38156

South Asian (SAS) AF: 0.00227 AC: 188 AN: 82830

European-Finnish (FIN) AF: 0.00474 AC: 239 AN: 50416

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.000610 AC: 671 AN: 1100034

Other (OTH) AF: 0.000572 AC: 34 AN: 59476

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152332 Hom.: 1 Cov.: 34 AF XY: 0.00136 AC XY: 101 AN XY: 74492

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15310

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

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00611 AC: 65 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.20
DANN	Benign	0.75
PhyloP100		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145615931; hg19: chr8-145740619;