rs199773279

chr8-144516364-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):c.755C>T(p.Pro252Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,610,090 control chromosomes in the GnomAD database, including 128 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. P252S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (11 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (117 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.618

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=0.005003482).
• BP6: Variant 8-144516364-G-A is Benign according to our data. Variant chr8-144516364-G-A is described in ClinVar as [Benign]. Clinvar id is 135165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144516364-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00143 (218/152338) while in subpopulation SAS AF= 0.0435 (210/4826). AF 95% confidence interval is 0.0387. There are 11 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.755C>T	p.Pro252Leu	missense_variant	5/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.755C>T	p.Pro252Leu	missense_variant	5/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.-317C>T		5_prime_UTR_variant	4/20	1
RECQL4	ENST00000524998.1	c.278C>T	p.Pro93Leu	missense_variant	3/4	3
RECQL4	ENST00000534538.1	c.*559C>T		3_prime_UTR_variant, NMD_transcript_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152220 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00532 AC: 1298 AN: 243952 Hom.: 46 AF XY: 0.00689 AC XY: 918 AN XY: 133216

Gnomad AFR exome AF: 0.0000667

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000168

Gnomad SAS exome AF: 0.0416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000721

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00254 AC: 3708 AN: 1457752 Hom.: 117 Cov.: 64 AF XY: 0.00368 AC XY: 2668 AN XY: 725140

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000477

Gnomad4 OTH exome AF: 0.00318

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152338 Hom.: 11 Cov.: 34 AF XY: 0.00216 AC XY: 161 AN XY: 74502

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.00613 AC: 739

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2021

- -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	8.0
Dann	Benign	0.73
DEOGEN2	Benign	0.073	T
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0050	T
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.011	B
Vest4		0.19
MVP		0.70
GERP RS		-0.014
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.028
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs199773279; hg19: chr8-145741748;