rs1060501379

chr8-144514260-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004260.4(RECQL4):c.1807T>C(p.Cys603Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. C603C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1807T>C	p.Cys603Arg	missense_variant	11/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1807T>C	p.Cys603Arg	missense_variant	11/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.736T>C	p.Cys246Arg	missense_variant	10/20	1
RECQL4	ENST00000534626.6	c.178T>C	p.Cys60Arg	missense_variant	2/8	5
RECQL4	ENST00000532846.2	c.664T>C	p.Cys222Arg	missense_variant	7/9	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 18, 2016

This sequence change replaces cysteine with arginine at codon 603 of the RECQL4 protein (p.Cys603Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RECQL4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Pathogenic	27
Dann	Benign	0.87
DEOGEN2	Benign	0.21	T;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.85	D;D
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.90
MVP		0.40
GERP RS		5.4
Varity_R		0.98
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501379; hg19: chr8-145739644;