rs1554900626

Variant names:

• chr8-144514968-C-G
• rs1554900626
• NM_004260.4:c.1588G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144514968-C-G
• chr8-144514968-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004260.4(RECQL4):​c.1588G>C​(p.Val530Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V530I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.838
• 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]

RECQL4 Gene-Disease associations (from GenCC):

• Baller-Gerold syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet
• Rothmund-Thomson syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Rothmund-Thomson syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P
• osteosarcoma

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• rapadilino syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 29 uncertain in NM_004260.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28877681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RECQL4	NM_004260.4	c.1588G>C	p.Val530Leu	missense_variant	Exon 9 of 21	ENST00000617875.6	NP_004251.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RECQL4	ENST00000617875.6	c.1588G>C	p.Val530Leu	missense_variant	Exon 9 of 21	1	NM_004260.4	ENSP00000482313.2
RECQL4	ENST00000621189.4	c.517G>C	p.Val173Leu	missense_variant	Exon 8 of 20	1		ENSP00000483145.1
RECQL4	ENST00000532846.2	c.442G>C	p.Val148Leu	missense_variant	Exon 5 of 9	5		ENSP00000476551.1
RECQL4	ENST00000688394.1	n.611G>C		non_coding_transcript_exon_variant	Exon 3 of 4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	0.0037	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	3.8
DANN	Benign	0.75
DEOGEN2	Benign	0.051	T;T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.29	T;T
PhyloP100		-0.84
PrimateAI	Benign	0.27	T
Sift4G	Uncertain	0.016	D;D
Polyphen		0.43	.;B
Vest4		0.57
MVP		0.28
GERP RS		-2.0
PromoterAI		-0.0026	Neutral
Varity_R		0.26
gMVP		0.48
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554900626; hg19: chr8-145740352;