chr8-144515846-A-T

Variant names:

• chr8-144515846-A-T
• rs1054027953
• NM_004260.4:c.1176T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001413041.1(RECQL4):​c.43T>A​(p.Trp15Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W15C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_001413041.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.28
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 17 uncertain in NM_001413041.1
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413041.1. 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.1176T>A	p.Gly392Gly	synonymous	Exon 6 of 21	NP_004251.4
	RECQL4	NM_001413041.1		c.43T>A	p.Trp15Arg	missense	Exon 5 of 19	NP_001399970.1
	RECQL4	NM_001413027.1		c.43T>A	p.Trp15Arg	missense	Exon 6 of 21	NP_001399956.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.1176T>A	p.Gly392Gly	synonymous	Exon 6 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.105T>A	p.Gly35Gly	synonymous	Exon 5 of 20	ENSP00000483145.1
	RECQL4	ENST00000887977.1		c.1176T>A	p.Gly392Gly	synonymous	Exon 6 of 21	ENSP00000558036.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.45
PhyloP100		-4.3
PromoterAI		0.047	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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: rs1054027953; hg19: chr8-145741230;