chr8-144513136-G-T

Variant names:

• chr8-144513136-G-T
• rs767528470
• NM_004260.4:c.2466C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004260.4(RECQL4):​c.2466C>A​(p.Gly822Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000635 in 1,259,690 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. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. G822G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: RECQL4 NM_004260.4 splice_region, synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.02
• 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, 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• osteosarcoma

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000265393 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-144513136-G-T is Benign according to our data. Variant chr8-144513136-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1142665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.02 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.2466C>A	p.Gly822Gly	splice_region synonymous	Exon 15 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2466C>A	p.Gly822Gly	splice_region synonymous	Exon 15 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2466C>A	p.Gly822Gly	splice_region synonymous	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.2466C>A	p.Gly822Gly	splice_region synonymous	Exon 15 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1395C>A	p.Gly465Gly	splice_region synonymous	Exon 14 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2373C>A	p.Gly791Gly	splice_region synonymous	Exon 15 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000100 AC: 2 AN: 199260 AF XY: 0.0000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000635 AC: 8 AN: 1259690 Hom.: 0 Cov.: 66 AF XY: 0.0000113 AC XY: 7 AN XY: 619016

African (AFR) AF: 0.00 AC: 0 AN: 27032

American (AMR) AF: 0.00 AC: 0 AN: 36648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17306

East Asian (EAS) AF: 0.00 AC: 0 AN: 23586

South Asian (SAS) AF: 0.0000907 AC: 7 AN: 77146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34138

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4658

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 991208

Other (OTH) AF: 0.0000208 AC: 1 AN: 47968

GnomAD4 genome Cov.: 34

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
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0030
DANN	Benign	0.67
PhyloP100		-4.0
PromoterAI		-0.0023	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs767528470; hg19: chr8-145738519;