rs2721190

Positions:

• chr8-144517130-A-G
• chr8-144517130-A-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.274T>C​(p.Ser92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,612,104 control chromosomes in the GnomAD database, including 789,429 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 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. S92F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.98 (73726 hom., cov: 38)
  • Exomes 𝑓: 0.99 (715703 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.157

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=8.1035216E-7).
• BP6: Variant 8-144517130-A-G is Benign according to our data. Variant chr8-144517130-A-G is described in ClinVar as [Benign]. Clinvar id is 135161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144517130-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.274T>C	p.Ser92Pro	missense_variant	4/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.274T>C	p.Ser92Pro	missense_variant	4/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.983 AC: 149666 AN: 152260 Hom.: 73665 Cov.: 38

Gnomad AFR AF: 0.983

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.998

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.986

GnomAD3 exomes AF: 0.970 AC: 237760 AN: 245198 Hom.: 115679 AF XY: 0.975 AC XY: 130847 AN XY: 134138

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.902

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 0.803

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.997

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.989 AC: 1444084 AN: 1459726 Hom.: 715703 Cov.: 73 AF XY: 0.990 AC XY: 718854 AN XY: 726162

Gnomad4 AFR exome AF: 0.984

Gnomad4 AMR exome AF: 0.908

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.989

GnomAD4 genome AF: 0.983 AC: 149786 AN: 152378 Hom.: 73726 Cov.: 38 AF XY: 0.982 AC XY: 73148 AN XY: 74516

Gnomad4 AFR AF: 0.983

Gnomad4 AMR AF: 0.949

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.997

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.986

Alfa AF: 0.994 Hom.: 68224

Bravo AF: 0.978

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.986 AC: 3869

ESP6500EA AF: 0.999 AC: 8276

ExAC AF: 0.973 AC: 116620

Asia WGS AF: 0.945 AC: 3285 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baller-Gerold syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 02, 2012	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Rapadilino syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.5
DANN	Benign	0.45
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	8.1e-7	T
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.39	T
Vest4		0.041
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.14

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: rs2721190; hg19: chr8-145742514; COSMIC: COSV52881402; COSMIC: COSV52881402;