17-75627670-C-T

Variant names:

• chr17-75627670-C-T
• rs200535477
• NM_004259.7:c.2828G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 6.21
• Publications: 16 publications found

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]

RECQL5 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• coronary artery disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 719399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004259.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL5	NM_004259.7	MANE Select	c.2828G>A	p.Arg943His	missense	Exon 19 of 20	NP_004250.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL5	ENST00000317905.10	TSL:1 MANE Select	c.2828G>A	p.Arg943His	missense	Exon 19 of 20	ENSP00000317636.5	O94762-1
	RECQL5	ENST00000423245.6	TSL:1	c.2747G>A	p.Arg916His	missense	Exon 19 of 20	ENSP00000394820.2	O94762-4
	RECQL5	ENST00000443199.6	TSL:1	n.2364G>A		non_coding_transcript_exon	Exon 12 of 13

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

GnomAD2 exomes AF: 0.00416 AC: 991 AN: 238364 AF XY: 0.00423

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 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

African (AFR) AF: 0.000688 AC: 23 AN: 33430

American (AMR) AF: 0.000365 AC: 16 AN: 43786

Ashkenazi Jewish (ASJ) AF: 0.000845 AC: 22 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85644

European-Finnish (FIN) AF: 0.00924 AC: 489 AN: 52930

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.00497 AC: 5517 AN: 1109688

Other (OTH) AF: 0.00344 AC: 207 AN: 60248

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

African (AFR) AF: 0.000795 AC: 33 AN: 41528

American (AMR) AF: 0.000327 AC: 5 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4812

European-Finnish (FIN) AF: 0.00820 AC: 87 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00456 AC: 310 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00429 Hom.: 5

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	RECQL5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	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
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

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