rs34948955

Variant names:

• chr8-144515238-C-T
• rs34948955
• NM_004260.4:c.1395G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004260.4(RECQL4):​c.1395G>A​(p.Thr465Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,591,106 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0071 (56 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.61
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-144515238-C-T is Benign according to our data. Variant chr8-144515238-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.61 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0053 (808/152336) while in subpopulation NFE AF = 0.0092 (626/68014). AF 95% confidence interval is 0.00861. There are 7 homozygotes in GnomAd4. There are 322 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1395G>A	p.Thr465Thr	synonymous	Exon 8 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.1395G>A	p.Thr465Thr	synonymous	Exon 8 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1395G>A	p.Thr465Thr	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.1395G>A	p.Thr465Thr	synonymous	Exon 8 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.324G>A	p.Thr108Thr	synonymous	Exon 7 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.1302G>A	p.Thr434Thr	synonymous	Exon 8 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 808 AN: 152218 Hom.: 7 Cov.: 34

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00542 AC: 1156 AN: 213264 AF XY: 0.00539

Gnomad AFR exome AF: 0.000734

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00825

Gnomad EAS exome AF: 0.0000659

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.00919

Gnomad OTH exome AF: 0.00814

GnomAD4 exome AF: 0.00709 AC: 10203 AN: 1438770 Hom.: 56 Cov.: 33 AF XY: 0.00703 AC XY: 5018 AN XY: 713812

African (AFR) AF: 0.00125 AC: 41 AN: 32896

American (AMR) AF: 0.00151 AC: 62 AN: 41150

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 259 AN: 25728

East Asian (EAS) AF: 0.0000522 AC: 2 AN: 38330

South Asian (SAS) AF: 0.00117 AC: 97 AN: 83208

European-Finnish (FIN) AF: 0.00373 AC: 189 AN: 50604

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.00834 AC: 9191 AN: 1101518

Other (OTH) AF: 0.00606 AC: 361 AN: 59590

GnomAD4 genome AF: 0.00530 AC: 808 AN: 152336 Hom.: 7 Cov.: 34 AF XY: 0.00432 AC XY: 322 AN XY: 74490

African (AFR) AF: 0.00132 AC: 55 AN: 41576

American (AMR) AF: 0.00222 AC: 34 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00920 AC: 626 AN: 68014

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00817 Hom.: 2

Bravo AF: 0.00477

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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 (2)
-	-	1	Baller-Gerold syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.030
DANN	Benign	0.72
PhyloP100		-2.6
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: rs34948955; hg19: chr8-145740622; COSMIC: COSV52881829; COSMIC: COSV52881829;