NM_004260.4:c.3393+9A>G

Variant names:

• chr8-144511902-T-C
• rs4251692
• NM_004260.4:c.3393+9A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.3393+9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,610,494 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 34)
  • Exomes 𝑓: 0.027 (634 hom.)
• Consequence: RECQL4 NM_004260.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.998
• Publications: 5 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 8-144511902-T-C is Benign according to our data. Variant chr8-144511902-T-C is described in ClinVar as Benign. ClinVar VariationId is 259260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (3089/152362) while in subpopulation NFE AF = 0.0279 (1895/68026). AF 95% confidence interval is 0.0268. There are 51 homozygotes in GnomAd4. There are 1483 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.3393+9A>G		intron	N/A	NP_004251.4
	RECQL4	NM_001413036.1		c.3402A>G	p.Ala1134Ala	splice_region synonymous	Exon 19 of 21	NP_001399965.1
	RECQL4	NM_001413019.1		c.3468+9A>G		intron	N/A	NP_001399948.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.3393+9A>G		intron	N/A	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.2322+9A>G		intron	N/A	ENSP00000483145.1
	RECQL4	ENST00000531875.2	TSL:5	c.648A>G	p.Ala216Ala	splice_region synonymous	Exon 4 of 6	ENSP00000477910.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3089 AN: 152244 Hom.: 51 Cov.: 34

Gnomad AFR AF: 0.00593

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0231 AC: 5664 AN: 245642 AF XY: 0.0232

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0761

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0377

Gnomad NFE exome AF: 0.0296

Gnomad OTH exome AF: 0.0297

GnomAD4 exome AF: 0.0270 AC: 39370 AN: 1458132 Hom.: 634 Cov.: 36 AF XY: 0.0267 AC XY: 19373 AN XY: 725394

African (AFR) AF: 0.00475 AC: 159 AN: 33472

American (AMR) AF: 0.0142 AC: 636 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 1977 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.00477 AC: 411 AN: 86246

European-Finnish (FIN) AF: 0.0371 AC: 1864 AN: 50250

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5766

European-Non Finnish (NFE) AF: 0.0292 AC: 32437 AN: 1111546

Other (OTH) AF: 0.0295 AC: 1781 AN: 60324

GnomAD4 genome AF: 0.0203 AC: 3089 AN: 152362 Hom.: 51 Cov.: 34 AF XY: 0.0199 AC XY: 1483 AN XY: 74512

African (AFR) AF: 0.00592 AC: 246 AN: 41588

American (AMR) AF: 0.0131 AC: 201 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 267 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00517 AC: 25 AN: 4834

European-Finnish (FIN) AF: 0.0380 AC: 404 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0279 AC: 1895 AN: 68026

Other (OTH) AF: 0.0198 AC: 42 AN: 2116

Alfa AF: 0.0247 Hom.: 52

Bravo AF: 0.0193

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Baller-Gerold syndrome Benign:1

Oct 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.19
DANN	Benign	0.54
PhyloP100		-1.0
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 0

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

Other links and lift over

dbSNP: rs4251692; hg19: chr8-145737285; COSMIC: COSV56742465;