rs766312203

chr8-144513260-ACGCCCGGCC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_004260.4(RECQL4):c.2412_2420del(p.Ala805_Arg807del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000559 in 1,590,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R804R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: RECQL4 NM_004260.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.54

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004260.4.
• PP5: Variant 8-144513260-ACGCCCGGCC-A is Pathogenic according to our data. Variant chr8-144513260-ACGCCCGGCC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.2412_2420del	p.Ala805_Arg807del	inframe_deletion	14/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.2412_2420del	p.Ala805_Arg807del	inframe_deletion	14/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.1341_1349del	p.Ala448_Arg450del	inframe_deletion	13/20	1
	ENST00000580385.1	n.272-343_272-335del		intron_variant, non_coding_transcript_variant		3
RECQL4	ENST00000534626.6	c.635-131_635-123del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151322 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000635

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.0000412 AC: 9 AN: 218562 Hom.: 0 AF XY: 0.0000328 AC XY: 4 AN XY: 121854

Gnomad AFR exome AF: 0.000543

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000580

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000403 AC: 58 AN: 1439460 Hom.: 0 AF XY: 0.0000335 AC XY: 24 AN XY: 715362

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000167

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151436 Hom.: 0 Cov.: 33 AF XY: 0.000243 AC XY: 18 AN XY: 73998

Gnomad4 AFR AF: 0.000634

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000477

Alfa AF: 0.000253 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baller-Gerold syndrome;C1849453:Rapadilino syndrome;C5203410:Rothmund-Thomson syndrome type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 26, 2022

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 22, 2021

Identified in unrelated patients with RECQL4-related phenotype referred for genetic testing at GeneDx and in published literature (Colombo et al., 2018); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29642415, 31604778) -

Rothmund-Thomson syndrome type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 26, 2021

ACMG classification criteria: PS4 supporting, PM2 moderate, PM3 moderate, PM4 moderate -

Baller-Gerold syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This variant, c.2412_2420del, results in the deletion of 3 amino acid(s) of the RECQL4 protein (p.Ala805_Arg807del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766312203, gnomAD 0.06%). This variant has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 29642415, 31604778; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 239724). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

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: rs766312203; hg19: chr8-145738643;