8-144515401-G-C

Variant names:

• chr8-144515401-G-C
• rs776349086
• NM_004260.4:c.1315C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004260.4(RECQL4):​c.1315C>G​(p.Pro439Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P439L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10767141).

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.1315C>G	p.Pro439Ala	missense	Exon 7 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.1315C>G	p.Pro439Ala	missense	Exon 7 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1315C>G	p.Pro439Ala	missense	Exon 7 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.1315C>G	p.Pro439Ala	missense	Exon 7 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.244C>G	p.Pro82Ala	missense	Exon 6 of 20	ENSP00000483145.1
	RECQL4	ENST00000532846.2	TSL:5	c.199C>G	p.Pro67Ala	missense	Exon 3 of 9	ENSP00000476551.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460460 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726504

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111810

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	10
DANN	Benign	0.52
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.11	T
PhyloP100		1.3
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.14	T
Polyphen		0.93	P
Vest4		0.16
MVP		0.73
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.37
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs776349086; hg19: chr8-145740785;