rs202203322

Positions:

• chr8-144512237-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004260.4(RECQL4):​c.3143A>G​(p.Lys1048Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,612,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -1.12

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015715122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.3143A>G	p.Lys1048Arg	missense_variant	18/21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.3143A>G	p.Lys1048Arg	missense_variant	18/21	1	NM_004260.4	ENSP00000482313	P1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152134 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000241

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: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000437 AC: 108 AN: 247156 Hom.: 0 AF XY: 0.000452 AC XY: 61 AN XY: 134850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.000816

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000384 AC: 560 AN: 1460032 Hom.: 0 Cov.: 68 AF XY: 0.000416 AC XY: 302 AN XY: 726296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000654

Gnomad4 NFE exome AF: 0.000456

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152134 Hom.: 0 Cov.: 36 AF XY: 0.000417 AC XY: 31 AN XY: 74312

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000707 Hom.: 1

Bravo AF: 0.000355

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000715 AC: 6

ExAC AF: 0.000499 AC: 60

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Nov 03, 2021

- -

RECQL4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2024

The RECQL4 c.3143A>G variant is predicted to result in the amino acid substitution p.Lys1048Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.084% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed in ClinVar with conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/407025). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Nov 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.025
DANN	Benign	0.52
DEOGEN2	Benign	0.0079	T;T;T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.55	T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.016	T;T;T
MutationAssessor	Benign	-0.30	.;N;.
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.050
MVP		0.77
GERP RS		-11
Varity_R		0.055
gMVP		0.47

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: rs202203322; hg19: chr8-145737620;