NM_004260.4:c.2112C>A

Variant names:

• chr8-144513659-G-T
• rs368140492
• NM_004260.4:c.2112C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_004260.4(RECQL4):​c.2112C>A​(p.Ile704Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,738 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I704I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.209
• 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: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 8-144513659-G-T is Benign according to our data. Variant chr8-144513659-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1129827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.

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.2112C>A	p.Ile704Ile	synonymous	Exon 13 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2112C>A	p.Ile704Ile	synonymous	Exon 13 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2112C>A	p.Ile704Ile	synonymous	Exon 13 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2112C>A	p.Ile704Ile	synonymous	Exon 13 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1041C>A	p.Ile347Ile	synonymous	Exon 12 of 20	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.480C>A	p.Ile160Ile	synonymous	Exon 4 of 8	ENSP00000477457.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415738 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 700218

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

African (AFR) AF: 0.00 AC: 0 AN: 32396

American (AMR) AF: 0.00 AC: 0 AN: 37426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37052

South Asian (SAS) AF: 0.00 AC: 0 AN: 80842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.18e-7 AC: 1 AN: 1088962

Other (OTH) AF: 0.00 AC: 0 AN: 58760

⚠️ 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 Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4: PM2:Supporting, BP4, BP7

Baller-Gerold syndrome Benign:1

Nov 25, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.62
CADD	Benign	3.2
DANN	Benign	0.84
PhyloP100		-0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368140492; hg19: chr8-145739043;