17-75627670-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004259.7(RECQL5):c.2828G>A(p.Arg943His) variant causes a missense change. The variant allele was found at a frequency of 0.00418 in 1,609,356 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts 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. R943C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (19 hom.)
• Consequence: RECQL5 NM_004259.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.21

Genes affected

RECQL5 (HGNC:9950): (RecQ like helicase 5) The protein encoded by this gene is a helicase that is important for genome stability. The encoded protein also prevents aberrant homologous recombination by displacing RAD51 from ssDNA. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012054294).
• BP6: Variant 17-75627670-C-T is Benign according to our data. Variant chr17-75627670-C-T is described in ClinVar as [Benign]. Clinvar id is 719399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL5	NM_004259.7	c.2828G>A	p.Arg943His	missense_variant	19/20	ENST00000317905.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL5	ENST00000317905.10	c.2828G>A	p.Arg943His	missense_variant	19/20	1	NM_004259.7	P1

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152112 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00416 AC: 991 AN: 238364 Hom.: 6 AF XY: 0.00423 AC XY: 549 AN XY: 129734

Gnomad AFR exome AF: 0.000906

Gnomad AMR exome AF: 0.000301

Gnomad ASJ exome AF: 0.000408

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00980

Gnomad NFE exome AF: 0.00684

Gnomad OTH exome AF: 0.00393

GnomAD4 exome AF: 0.00431 AC: 6286 AN: 1457126 Hom.: 19 Cov.: 31 AF XY: 0.00426 AC XY: 3083 AN XY: 724376

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.000365

Gnomad4 ASJ exome AF: 0.000845

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00924

Gnomad4 NFE exome AF: 0.00497

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00292 AC: 444 AN: 152230 Hom.: 1 Cov.: 33 AF XY: 0.00287 AC XY: 214 AN XY: 74438

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.00456

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00406 Hom.: 2

Bravo AF: 0.00218

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000470 AC: 2

ESP6500EA AF: 0.00436 AC: 37

ExAC AF: 0.00573 AC: 693

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RECQL5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	31
Dann	Benign	0.97
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Uncertain	0.28	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
REVEL	Pathogenic	0.66
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.59
MVP		0.93
MPC		0.62
ClinPred		0.042	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.41

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: rs200535477; hg19: chr17-73623750; COSMIC: COSV58640177; COSMIC: COSV58640177;