rs757678397

Variant names:

• chr8-144517757-G-A
• rs757678397
• NM_004260.4:c.28C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144517757-G-A
• chr8-144517757-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004260.4(RECQL4):​c.28C>T​(p.Arg10Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000534 in 1,311,306 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. R10Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.27
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12372607).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.28C>T	p.Arg10Trp	missense	Exon 1 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.28C>T	p.Arg10Trp	missense	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.28C>T	p.Arg10Trp	missense	Exon 1 of 21	NP_001399965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.28C>T	p.Arg10Trp	missense	Exon 1 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.-1109C>T		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1
	LRRC14	ENST00000292524.6	TSL:1 MANE Select	c.-396G>A		upstream_gene	N/A	ENSP00000292524.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150894 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

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: 0.00000431 AC: 5 AN: 1160412 Hom.: 0 Cov.: 32 AF XY: 0.00000532 AC XY: 3 AN XY: 564374

African (AFR) AF: 0.00 AC: 0 AN: 23158

American (AMR) AF: 0.00 AC: 0 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17314

East Asian (EAS) AF: 0.0000812 AC: 2 AN: 24628

South Asian (SAS) AF: 0.0000222 AC: 1 AN: 45048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3202

European-Non Finnish (NFE) AF: 0.00000208 AC: 2 AN: 959900

Other (OTH) AF: 0.00 AC: 0 AN: 46138

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150894 Hom.: 0 Cov.: 34 AF XY: 0.0000136 AC XY: 1 AN XY: 73628

African (AFR) AF: 0.0000242 AC: 1 AN: 41302

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67590

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000822 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R10W variant (also known as c.28C>T), located in coding exon 1 of the RECQL4 gene, results from a C to T substitution at nucleotide position 28. The arginine at codon 10 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.

not provided Uncertain:1

Jan 05, 2023

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RECQL4 gene demonstrated a sequence change, c.28C>T, in exon 1 that results in an amino acid change, p.Arg10Trp. This sequence change does not appear to have been previously described in individuals with RECQL4-related disorders. This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0034% (dbSNP rs757678397). The p.Arg10Trp change affects a poorly conserved amino acid residue located in a domain of the RECQL4 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg10Trp substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg10Trp change remains unknown at this time.

Baller-Gerold syndrome Uncertain:1

Oct 24, 2023

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 10 of the RECQL4 protein (p.Arg10Trp). This variant is present in population databases (rs757678397, gnomAD 0.01%). 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: 566753). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.061	T
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.12	T
PhyloP100		1.3
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.033	D
Polyphen		0.031	B
Vest4		0.17
MVP		0.67
GERP RS		2.5
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.75
gMVP		0.14
Mutation Taster		=88/12	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: rs757678397; hg19: chr8-145743141;