rs767337200

Variant names:

• chr8-144515194-G-A
• rs767337200
• NM_004260.4:c.1439C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144515194-G-A
• chr8-144515194-G-C
• chr8-144515194-G-T

Variant summary

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

The NM_004260.4(RECQL4):​c.1439C>T​(p.Ala480Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000706 in 1,417,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/13 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: 7.1e-7 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.75

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37964764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1439C>T	p.Ala480Val	missense_variant	Exon 8 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1439C>T	p.Ala480Val	missense_variant	Exon 8 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.368C>T	p.Ala123Val	missense_variant	Exon 7 of 20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.323C>T	p.Ala108Val	missense_variant	Exon 4 of 9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.462C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 181336 Hom.: 0 AF XY: 0.0000205 AC XY: 2 AN XY: 97538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000262

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1417378 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 701220

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000839 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A480V variant (also known as c.1439C>T), located in coding exon 8 of the RECQL4 gene, results from a C to T substitution at nucleotide position 1439. The alanine at codon 480 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Baller-Gerold syndrome Uncertain:1

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 480 of the RECQL4 protein (p.Ala480Val). This variant is present in population databases (rs767337200, gnomAD 0.003%). 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: 566077). 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 expected to disrupt RECQL4 protein function with a positive 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	Benign	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Benign	0.69
DEOGEN2	Benign	0.033	T;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.38	T;T
PrimateAI	Benign	0.36	T
Sift4G	Uncertain	0.038	D;D
Polyphen		0.40	.;B
Vest4		0.47
MVP		0.67
GERP RS		5.4
Varity_R		0.14
gMVP		0.33

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: rs767337200; hg19: chr8-145740578;