chr8-144513209-GGT-G

Variant names:

• chr8-144513209-GGT-G
• rs750392035
• NM_004260.4:c.2463+7_2463+8delAC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004260.4(RECQL4):​c.2463+7_2463+8delAC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL4 NM_004260.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 0 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, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 8-144513209-GGT-G is Benign according to our data. Variant chr8-144513209-GGT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 239731.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2463+7_2463+8delAC		splice_region intron	N/A	NP_004251.4
	RECQL4	NM_001413019.1		c.2463+7_2463+8delAC		splice_region intron	N/A	NP_001399948.1
	RECQL4	NM_001413036.1		c.2463+7_2463+8delAC		splice_region intron	N/A	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2463+7_2463+8delAC		splice_region intron	N/A	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1392+7_1392+8delAC		splice_region intron	N/A	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2370+7_2370+8delAC		splice_region intron	N/A	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 304 AN: 146940 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000988

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.00299

Gnomad ASJ AF: 0.00176

Gnomad EAS AF: 0.00202

Gnomad SAS AF: 0.00402

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00502

GnomAD2 exomes AF: 0.00571 AC: 971 AN: 169988 AF XY: 0.00656

Gnomad AFR exome AF: 0.00371

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00260

Gnomad FIN exome AF: 0.00971

Gnomad NFE exome AF: 0.00598

Gnomad OTH exome AF: 0.00286

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00122 AC: 1670 AN: 1371710 Hom.: 0 AF XY: 0.00153 AC XY: 1037 AN XY: 676684

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00108 AC: 35 AN: 32354

American (AMR) AF: 0.00494 AC: 205 AN: 41526

Ashkenazi Jewish (ASJ) AF: 0.00296 AC: 70 AN: 23628

East Asian (EAS) AF: 0.00212 AC: 81 AN: 38192

South Asian (SAS) AF: 0.00528 AC: 414 AN: 78390

European-Finnish (FIN) AF: 0.00210 AC: 75 AN: 35702

Middle Eastern (MID) AF: 0.00205 AC: 10 AN: 4888

European-Non Finnish (NFE) AF: 0.000665 AC: 705 AN: 1059798

Other (OTH) AF: 0.00131 AC: 75 AN: 57232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00207 AC: 305 AN: 147020 Hom.: 0 Cov.: 20 AF XY: 0.00244 AC XY: 174 AN XY: 71434

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000986 AC: 40 AN: 40580

American (AMR) AF: 0.00299 AC: 44 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 6 AN: 3410

East Asian (EAS) AF: 0.00203 AC: 10 AN: 4934

South Asian (SAS) AF: 0.00403 AC: 18 AN: 4466

European-Finnish (FIN) AF: 0.00235 AC: 23 AN: 9800

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00231 AC: 152 AN: 65894

Other (OTH) AF: 0.00497 AC: 10 AN: 2014

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00322 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Baller-Gerold syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs750392035; hg19: chr8-145738592; COSMIC: COSV52879022; COSMIC: COSV52879022;