8-144514050-GTGTGGC-GTGTGGCTGTGGC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4

The NM_004260.4(RECQL4):c.1935_1936insGCCACA(p.Ala644_Thr645dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000769 in 1,430,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T645T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: RECQL4 NM_004260.4 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.992

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_004260.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004260.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RECQL4	NM_004260.4	c.1935_1936insGCCACA	p.Ala644_Thr645dup	inframe_insertion	12/21	ENST00000617875.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RECQL4	ENST00000617875.6	c.1935_1936insGCCACA	p.Ala644_Thr645dup	inframe_insertion	12/21	1	NM_004260.4	P1
RECQL4	ENST00000621189.4	c.864_865insGCCACA	p.Ala287_Thr288dup	inframe_insertion	11/20	1
RECQL4	ENST00000532846.2	c.790_791insGCCACA	p.Ala263_Thr264dup	inframe_insertion	8/9	5
RECQL4	ENST00000534626.6	c.304_305insGCCACA	p.Ala101_Thr102dup	inframe_insertion	3/8	5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000769 AC: 11 AN: 1430902 Hom.: 0 Cov.: 36 AF XY: 0.00000846 AC XY: 6 AN XY: 709276

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000820

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baller-Gerold syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 26, 2022

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has been observed in individual(s) with Rothmund-Thomson syndrome (PMID: 27247962). This variant is not present in population databases (gnomAD no frequency). This variant, c.1930_1935dup, is a complex sequence change that results in the insertion of 2 amino acid(s) in the RECQL4 protein (p.Ala644_Thr645dup). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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: rs781471399; hg19: chr8-145739434;