chr8-144513027-TGGTGCA-T

Variant names:

• chr8-144513027-TGGTGCA-T
• rs548804317
• NM_004260.4:c.2569_2574delTGCACC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_004260.4(RECQL4):​c.2569_2574delTGCACC​(p.Cys857_Thr858del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,574,460 control chromosomes in the GnomAD database, including 41 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (38 hom.)
• Consequence: RECQL4 NM_004260.4 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.833

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]

ENSG00000265393 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004260.4.
• BP6: Variant 8-144513027-TGGTGCA-T is Benign according to our data. Variant chr8-144513027-TGGTGCA-T is described in ClinVar as [Likely_benign]. Clinvar id is 135140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-144513027-TGGTGCA-T is described in Lovd as [Likely_benign]. Variant chr8-144513027-TGGTGCA-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0024 (365/152314) while in subpopulation AMR AF= 0.015 (229/15306). AF 95% confidence interval is 0.0134. There are 3 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.2569_2574delTGCACC	p.Cys857_Thr858del	conservative_inframe_deletion	Exon 15 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.2569_2574delTGCACC	p.Cys857_Thr858del	conservative_inframe_deletion	Exon 15 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.1498_1503delTGCACC	p.Cys500_Thr501del	conservative_inframe_deletion	Exon 14 of 20	1		ENSP00000483145.1
RECQL4	ENST00000534626.6	c.739_744delTGCACC	p.Cys247_Thr248del	conservative_inframe_deletion	Exon 6 of 8	5		ENSP00000477457.1
ENSG00000265393	ENST00000580385.1	n.271+205_271+210delTGCAGG		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152196 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00737 AC: 1382 AN: 187612 Hom.: 30 AF XY: 0.00575 AC XY: 584 AN XY: 101586

Gnomad AFR exome AF: 0.000983

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.000797

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000997

Gnomad OTH exome AF: 0.00403

GnomAD4 exome AF: 0.00149 AC: 2114 AN: 1422146 Hom.: 38 AF XY: 0.00136 AC XY: 958 AN XY: 703984

Gnomad4 AFR exome AF: 0.000614

Gnomad4 AMR exome AF: 0.0361

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0124

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152314 Hom.: 3 Cov.: 34 AF XY: 0.00244 AC XY: 182 AN XY: 74488

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0122

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.00503

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24728327) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RECQL4: PM4, BS1, BS2 -

Sep 12, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rothmund-Thomson syndrome type 2 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as BENIGN. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0215 - In-frame insertion/deletion fully contained in a repetitive region that has low conservation (exon 15). (P) 0251 - Variant is heterozygous. (N) 0306 - Variant is present in gnomAD >=0.03 and <0.05 for a recessive condition (1402 heterozygotes, 30 homozygotes). (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. Two Benign reports (ClinVar). (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not specified Benign:1 Other:1

Dec 20, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Rapadilino syndrome Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baller-Gerold syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 17, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs548804317; hg19: chr8-145738410;