chr8-144513211-T-C

Variant names:

• chr8-144513211-T-C
• rs767159855
• NM_004260.4:c.2463+7A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004260.4(RECQL4):​c.2463+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 906,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: RECQL4 NM_004260.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.11
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.2463+7A>G		splice_region intron	N/A	NP_004251.4
	RECQL4	NM_001413019.1		c.2463+7A>G		splice_region intron	N/A	NP_001399948.1
	RECQL4	NM_001413036.1		c.2463+7A>G		splice_region intron	N/A	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.2463+7A>G		splice_region intron	N/A	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1392+7A>G		splice_region intron	N/A	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.634-73A>G		intron	N/A	ENSP00000477457.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000331 AC: 3 AN: 906874 Hom.: 0 Cov.: 40 AF XY: 0.00000450 AC XY: 2 AN XY: 444064

⚠️ 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: 21540

American (AMR) AF: 0.00 AC: 0 AN: 26090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16304

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29630

South Asian (SAS) AF: 0.0000241 AC: 1 AN: 41518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2794

European-Non Finnish (NFE) AF: 0.00000142 AC: 1 AN: 703066

Other (OTH) AF: 0.00 AC: 0 AN: 39360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.28
DANN	Benign	0.50
PhyloP100		-3.1
PromoterAI		0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767159855; hg19: chr8-145738594;