8-144514311-C-A

Position:

• chr8-144514311-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000617875.6(RECQL4):​c.1756G>T​(p.Gly586Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,457,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G586E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RECQL4 ENST00000617875.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1756G>T	p.Gly586Trp	missense_variant	11/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1756G>T	p.Gly586Trp	missense_variant	11/21	1	NM_004260.4	ENSP00000482313	P1
RECQL4	ENST00000621189.4	c.685G>T	p.Gly229Trp	missense_variant	10/20	1		ENSP00000483145
RECQL4	ENST00000534626.6	c.127G>T	p.Gly43Trp	missense_variant	2/8	5		ENSP00000477457
RECQL4	ENST00000532846.2	c.613G>T	p.Gly205Trp	missense_variant	7/9	5		ENSP00000476551

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457486 Hom.: 0 Cov.: 36 AF XY: 0.00000966 AC XY: 7 AN XY: 724824

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.00

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

Labcorp Genetics (formerly Invitae), Labcorp

Dec 23, 2015

This sequence change replaces glycine with tryptophan at codon 586 of the RECQL4 protein (p.Gly586Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably damaging"; Align-GVGD: "C15"). In summary, this 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	Benign	0.32
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	18
DANN	Benign	0.67
DEOGEN2	Benign	0.21	T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.74	D;D
PrimateAI	Uncertain	0.50	T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.58
MVP		0.56
GERP RS		4.5
Varity_R		0.61
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs878854643; hg19: chr8-145739695;