chr8-144517763-G-A

Variant names:

• chr8-144517763-G-A
• rs1554905170
• NM_004260.4:c.22C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004260.4(RECQL4):​c.22C>T​(p.Arg8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000174 in 1,151,648 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.288
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32116038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.22C>T	p.Arg8Trp	missense_variant	Exon 1 of 21	ENST00000617875.6	NP_004251.4
LRRC14	NM_014665.4	c.-390G>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.22C>T	p.Arg8Trp	missense_variant	Exon 1 of 21	1	NM_004260.4	ENSP00000482313.2
LRRC14	ENST00000292524.6	c.-390G>A		upstream_gene_variant		1	NM_014665.4	ENSP00000292524.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000174 AC: 2 AN: 1151648 Hom.: 0 Cov.: 32 AF XY: 0.00000357 AC XY: 2 AN XY: 559524

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22922

American (AMR) AF: 0.00 AC: 0 AN: 14602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16990

East Asian (EAS) AF: 0.00 AC: 0 AN: 24322

South Asian (SAS) AF: 0.0000229 AC: 1 AN: 43680

European-Finnish (FIN) AF: 0.0000394 AC: 1 AN: 25374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3164

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 955010

Other (OTH) AF: 0.00 AC: 0 AN: 45584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R8W variant (also known as c.22C>T), located in coding exon 1 of the RECQL4 gene, results from a C to T substitution at nucleotide position 22. The arginine at codon 8 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Baller-Gerold syndrome Uncertain:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 8 of the RECQL4 protein (p.Arg8Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RECQL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 529007). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.32	T
PhyloP100		-0.29
PrimateAI	Pathogenic	0.93	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.65
GERP RS		1.5
PromoterAI		0.085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.37
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1554905170; hg19: chr8-145743147;