8-144512319-G-C

Variant names:

• chr8-144512319-G-C
• rs137853232
• NM_004260.4:c.3061C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_004260.4(RECQL4):​c.3061C>G​(p.Arg1021Gly) 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. 10/16 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. R1021Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-144512319-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.3061C>G	p.Arg1021Gly	missense	Exon 18 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.3136C>G	p.Arg1046Gly	missense	Exon 17 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3061C>G	p.Arg1021Gly	missense	Exon 18 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.3061C>G	p.Arg1021Gly	missense	Exon 18 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1990C>G	p.Arg664Gly	missense	Exon 17 of 20	ENSP00000483145.1
	RECQL4	ENST00000531875.2	TSL:5	c.307C>G	p.Arg103Gly	missense	Exon 3 of 6	ENSP00000477910.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.4
DANN	Benign	0.58
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.16	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.32
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.70
GERP RS		-0.32
PromoterAI		0.0075	Neutral
Varity_R		0.19
gMVP		0.53
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.65		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853232; hg19: chr8-145737702;