rs993147176

Positions:

• chr8-144514017-C-A
• chr8-144514017-C-G
• chr8-144514017-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.1969G>T​(p.Ala657Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000211 in 1,419,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.89

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38025144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1969G>T	p.Ala657Ser	missense_variant	12/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1969G>T	p.Ala657Ser	missense_variant	12/21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.898G>T	p.Ala300Ser	missense_variant	11/20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.337G>T	p.Ala113Ser	missense_variant	3/8	5		ENSP00000477457.1
RECQL4	ENST00000532846.2	c.823G>T	p.Ala275Ser	missense_variant	8/9	5		ENSP00000476551.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419434 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 702592

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: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2021

The c.1969G>T (p.A657S) alteration is located in exon 12 (coding exon 12) of the RECQL4 gene. This alteration results from a G to T substitution at nucleotide position 1969, causing the alanine (A) at amino acid position 657 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RECQL4 protein function. ClinVar contains an entry for this variant (Variation ID: 837409). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 657 of the RECQL4 protein (p.Ala657Ser). -

Baller-Gerold syndrome;C1849453:Rapadilino syndrome Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.73
DEOGEN2	Benign	0.0035	T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.38	T;T
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.17	T;T
Polyphen		0.057	.;B
Vest4		0.40
MVP		0.62
GERP RS		5.4
Varity_R		0.23
gMVP		0.35

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: rs993147176; hg19: chr8-145739401;