8-144513027-TGGTGCA-TGGTGCAGGTGCA

Variant names:

• chr8-144513027-T-TGGTGCA
• rs548804317
• NM_004260.4:c.2569_2574dupTGCACC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.2569_2574dupTGCACC​(p.Thr858_Arg859insCysThr) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,574,466 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T858T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: RECQL4 NM_004260.4 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.833
• 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

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004260.4.
• BP6: Variant 8-144513027-T-TGGTGCA is Benign according to our data. Variant chr8-144513027-T-TGGTGCA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00355 (540/152314) while in subpopulation AFR AF = 0.0064 (266/41574). AF 95% confidence interval is 0.00577. There are 1 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR,AD 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.2569_2574dupTGCACC	p.Thr858_Arg859insCysThr	conservative_inframe_insertion	Exon 15 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.2569_2574dupTGCACC	p.Thr858_Arg859insCysThr	conservative_inframe_insertion	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2569_2574dupTGCACC	p.Thr858_Arg859insCysThr	conservative_inframe_insertion	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.2569_2574dupTGCACC	p.Thr858_Arg859insCysThr	conservative_inframe_insertion	Exon 15 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.1498_1503dupTGCACC	p.Thr501_Arg502insCysThr	conservative_inframe_insertion	Exon 14 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.2476_2481dupTGCACC	p.Thr827_Arg828insCysThr	conservative_inframe_insertion	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152196 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00955

GnomAD2 exomes AF: 0.00195 AC: 365 AN: 187612 AF XY: 0.00189

Gnomad AFR exome AF: 0.00540

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00652

Gnomad EAS exome AF: 0.0000751

Gnomad FIN exome AF: 0.000114

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00302

GnomAD4 exome AF: 0.00255 AC: 3631 AN: 1422152 Hom.: 7 Cov.: 66 AF XY: 0.00248 AC XY: 1747 AN XY: 703988

African (AFR) AF: 0.00611 AC: 199 AN: 32558

American (AMR) AF: 0.00352 AC: 135 AN: 38372

Ashkenazi Jewish (ASJ) AF: 0.00712 AC: 181 AN: 25434

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37372

South Asian (SAS) AF: 0.000847 AC: 69 AN: 81492

European-Finnish (FIN) AF: 0.000183 AC: 9 AN: 49210

Middle Eastern (MID) AF: 0.00297 AC: 17 AN: 5724

European-Non Finnish (NFE) AF: 0.00259 AC: 2833 AN: 1093032

Other (OTH) AF: 0.00317 AC: 187 AN: 58958

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152314 Hom.: 1 Cov.: 34 AF XY: 0.00337 AC XY: 251 AN XY: 74486

African (AFR) AF: 0.00640 AC: 266 AN: 41574

American (AMR) AF: 0.00444 AC: 68 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68008

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00413

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	Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 (1)
-	-	1	Familial meningioma (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Rapadilino syndrome (1)
-	-	1	RECQL4-related disorder (1)
-	-	1	Rothmund-Thomson syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83
Mutation Taster		=87/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs548804317; hg19: chr8-145738410; COSMIC: COSV99468016; COSMIC: COSV99468016;