rs200516441

chr8-144517129-G-Achr8-144517129-G-C

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.275C>T(p.Ser92Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,184 control chromosomes in the GnomAD database, including 35 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. S92P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 34)
  • Exomes 𝑓: 0.00086 (21 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.0530

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=0.003534019).
• BP6: Variant 8-144517129-G-A is Benign according to our data. Variant chr8-144517129-G-A is described in ClinVar as [Benign]. Clinvar id is 197231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00814 (1240/152376) while in subpopulation AFR AF= 0.0284 (1182/41592). AF 95% confidence interval is 0.0271. There are 14 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.275C>T	p.Ser92Phe	missense_variant	4/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.275C>T	p.Ser92Phe	missense_variant	4/21	1	NM_004260.4	P1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 1240 AN: 152258 Hom.: 14 Cov.: 34

Gnomad AFR AF: 0.0285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00191 AC: 468 AN: 245212 Hom.: 6 AF XY: 0.00145 AC XY: 195 AN XY: 134150

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000544

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000859 AC: 1254 AN: 1459808 Hom.: 21 Cov.: 31 AF XY: 0.000738 AC XY: 536 AN XY: 726198

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00146

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152376 Hom.: 14 Cov.: 34 AF XY: 0.00791 AC XY: 589 AN XY: 74508

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00350 Hom.: 4

Bravo AF: 0.00947

ExAC AF: 0.00216 AC: 260

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2018	- -

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)	Dec 09, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	10
Dann	Benign	0.77
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0035	T
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.080	T
Vest4		0.22
MVP		0.34
GERP RS		3.1
Varity_R		0.044
gMVP		0.17

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: rs200516441; hg19: chr8-145742513; COSMIC: COSV52879526; COSMIC: COSV52879526;