17-75627462-C-T

Variant names:

• chr17-75627462-C-T
• rs201830334
• NM_004259.7:c.2936G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004259.7(RECQL5):​c.2936G>A​(p.Ser979Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,758 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: RECQL5 NM_004259.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.76

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06887603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL5	NM_004259.7	c.2936G>A	p.Ser979Asn	missense_variant	Exon 20 of 20	ENST00000317905.10	NP_004250.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL5	ENST00000317905.10	c.2936G>A	p.Ser979Asn	missense_variant	Exon 20 of 20	1	NM_004259.7	ENSP00000317636.5
RECQL5	ENST00000423245.6	c.2855G>A	p.Ser952Asn	missense_variant	Exon 20 of 20	1		ENSP00000394820.2

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000160 AC: 40 AN: 249426 Hom.: 1 AF XY: 0.000170 AC XY: 23 AN XY: 135382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000256

Gnomad OTH exome AF: 0.000660

GnomAD4 exome AF: 0.000144 AC: 211 AN: 1461418 Hom.: 1 Cov.: 31 AF XY: 0.000155 AC XY: 113 AN XY: 727006

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000127

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74484

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000540

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000491

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2936G>A (p.S979N) alteration is located in exon 20 (coding exon 19) of the RECQL5 gene. This alteration results from a G to A substitution at nucleotide position 2936, causing the serine (S) at amino acid position 979 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

RECQL5-related disorder Uncertain:1

Apr 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RECQL5 c.2936G>A variant is predicted to result in the amino acid substitution p.Ser979Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.095	.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.3	.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.20	.;N
REVEL	Benign	0.21
Sift	Benign	0.077	.;T
Sift4G	Benign	0.36	T;T
Polyphen		0.60	.;P
Vest4		0.23
MVP		0.73
MPC		0.13
ClinPred		0.043	T
GERP RS		5.2
Varity_R		0.10
gMVP		0.59

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: rs201830334; hg19: chr17-73623542; COSMIC: COSV100511959; COSMIC: COSV100511959;