rs745453660

chr8-144512149-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004260.4(RECQL4):c.3231T>A(p.Phe1077Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000653 in 1,607,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.839

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_004260.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24661642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.3231T>A	p.Phe1077Leu	missense_variant	18/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.3231T>A	p.Phe1077Leu	missense_variant	18/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152250 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000377 AC: 9 AN: 238974 Hom.: 0 AF XY: 0.0000229 AC XY: 3 AN XY: 130956

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000747

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000680 AC: 99 AN: 1454924 Hom.: 0 Cov.: 67 AF XY: 0.0000622 AC XY: 45 AN XY: 723108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000678

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: 0.0000857

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152250 Hom.: 0 Cov.: 35 AF XY: 0.0000403 AC XY: 3 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rothmund-Thomson syndrome type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 21, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 10, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1077 of the RECQL4 protein (p.Phe1077Leu). This variant is present in population databases (rs745453660, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 528915). 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 with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	16
Dann	Benign	0.79
DEOGEN2	Benign	0.027	T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.25	T;T;T
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.24	.;B;.
Vest4		0.68
MVP		0.26
GERP RS		-3.3
Varity_R		0.27
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745453660; hg19: chr8-145737532;