rs2721191

chr8-144514295-G-Achr8-144514295-G-Cchr8-144514295-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004260.4(RECQL4):c.1772C>T(p.Pro591Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00506 in 1,611,110 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P591H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (193 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (189 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 4.43

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023368).
• BP6: Variant 8-144514295-G-A is Benign according to our data. Variant chr8-144514295-G-A is described in ClinVar as [Benign]. Clinvar id is 135131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144514295-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1772C>T	p.Pro591Leu	missense_variant	11/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1772C>T	p.Pro591Leu	missense_variant	11/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.701C>T	p.Pro234Leu	missense_variant	10/20	1
RECQL4	ENST00000534626.6	c.143C>T	p.Pro48Leu	missense_variant	2/8	5
RECQL4	ENST00000532846.2	c.629C>T	p.Pro210Leu	missense_variant	7/9	5

Frequencies

GnomAD3 genomes AF: 0.0274 AC: 4171 AN: 152116 Hom.: 190 Cov.: 34

Gnomad AFR AF: 0.0959

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00909

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0229

GnomAD3 exomes AF: 0.00647 AC: 1577 AN: 243902 Hom.: 58 AF XY: 0.00491 AC XY: 655 AN XY: 133414

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00272 AC: 3965 AN: 1458876 Hom.: 189 Cov.: 36 AF XY: 0.00231 AC XY: 1678 AN XY: 725686

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00421

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.00501

GnomAD4 genome AF: 0.0275 AC: 4186 AN: 152234 Hom.: 193 Cov.: 34 AF XY: 0.0265 AC XY: 1971 AN XY: 74420

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00645 Hom.: 26

Bravo AF: 0.0318

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0837 AC: 350

ESP6500EA AF: 0.000474 AC: 4

ExAC AF: 0.00806 AC: 971

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000297

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2019

This variant is associated with the following publications: (PMID: 18504617) -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Sep 10, 2020

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	16
Dann	Benign	0.67
DEOGEN2	Benign	0.025	T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0023	T;T
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.18	T;D
Polyphen		0.0020	.;B
Vest4		0.28
MVP		0.74
GERP RS		4.5
Varity_R		0.18
gMVP		0.62

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: rs2721191; hg19: chr8-145739679; COSMIC: COSV52878609; COSMIC: COSV52878609;