8-144512247-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_004260.4(RECQL4):c.3133G>A(p.Ala1045Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000785 in 1,612,438 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1045A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 35)
  • Exomes 𝑓: 0.00049 (5 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0750

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045722723).
• BP6: Variant 8-144512247-C-T is Benign according to our data. Variant chr8-144512247-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144512247-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00364 (555/152320) while in subpopulation AFR AF= 0.0117 (488/41572). AF 95% confidence interval is 0.0109. There are 1 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.3133G>A	p.Ala1045Thr	missense_variant	18/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.3133G>A	p.Ala1045Thr	missense_variant	18/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152202 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00105 AC: 259 AN: 247204 Hom.: 1 AF XY: 0.000897 AC XY: 121 AN XY: 134864

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.000501

Gnomad EAS exome AF: 0.00139

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000487 AC: 711 AN: 1460118 Hom.: 5 Cov.: 67 AF XY: 0.000450 AC XY: 327 AN XY: 726330

Gnomad4 AFR exome AF: 0.0106

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.000957

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000989

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152320 Hom.: 1 Cov.: 35 AF XY: 0.00352 AC XY: 262 AN XY: 74480

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00386

ESP6500AA AF: 0.00881 AC: 36

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00122 AC: 147

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 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	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	RECQL4: BP4, BS1 -

Rothmund-Thomson syndrome type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

RECQL4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Baller-Gerold syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	10
Dann	Benign	0.72
DEOGEN2	Benign	0.012	T;T;T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0046	T;T;T
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.89	.;P;.
Vest4		0.097
MVP		0.69
GERP RS		2.4
Varity_R		0.025
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35348691; hg19: chr8-145737630;