chr8-144517775-G-A

Variant names:

• chr8-144517775-G-A
• rs878854640
• ENST00000621189.4:c.-1127C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001413023.1(RECQL4):​c.-1127C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,262,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: RECQL4 NM_001413023.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.309

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]

LRRC14 (HGNC:20419): (leucine rich repeat containing 14) This gene encodes a leucine-rich repeat-containing protein. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 8-144517775-G-A is Benign according to our data. Variant chr8-144517775-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 239692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.10C>T	p.Leu4Leu	synonymous_variant	Exon 1 of 21	ENST00000617875.6	NP_004251.4
LRRC14	NM_014665.4	c.-378G>A		upstream_gene_variant		ENST00000292524.6	NP_055480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.10C>T	p.Leu4Leu	synonymous_variant	Exon 1 of 21	1	NM_004260.4	ENSP00000482313.2
LRRC14	ENST00000292524.6	c.-378G>A		upstream_gene_variant		1	NM_014665.4	ENSP00000292524.1

Frequencies

GnomAD3 genomes AF: 0.000245 AC: 37 AN: 150754 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000872

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000234 AC: 26 AN: 1111306 Hom.: 0 Cov.: 32 AF XY: 0.0000280 AC XY: 15 AN XY: 535784

Gnomad4 AFR exome AF: 0.000852

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000751

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000245 AC: 37 AN: 150754 Hom.: 0 Cov.: 34 AF XY: 0.000204 AC XY: 15 AN XY: 73560

Gnomad4 AFR AF: 0.000872

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000272

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Nov 30, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Baller-Gerold syndrome Benign:1

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RECQL4-related disorder Benign:1

Aug 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.6
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs878854640; hg19: chr8-145743159;