8-144515164-A-C

Variant names:

• chr8-144515164-A-C
• rs1554900934
• NM_004260.4:c.1469T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001413043.1(RECQL4):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000708 in 1,413,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: RECQL4 NM_001413043.1 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.54
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 10 pathogenic variants. Next in-frame start position is after 48 codons. Genomic position: 144514947. Lost 0.066 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413043.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.1469T>G	p.Met490Arg	missense	Exon 8 of 21	NP_004251.4
	RECQL4	NM_001413043.1		c.2T>G	p.Met1?	start_lost	Exon 6 of 19	NP_001399972.1
	RECQL4	NM_001413019.1		c.1469T>G	p.Met490Arg	missense	Exon 8 of 20	NP_001399948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.1469T>G	p.Met490Arg	missense	Exon 8 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.398T>G	p.Met133Arg	missense	Exon 7 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.1376T>G	p.Met459Arg	missense	Exon 8 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413126 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 698524

African (AFR) AF: 0.0000311 AC: 1 AN: 32158

American (AMR) AF: 0.00 AC: 0 AN: 37170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25362

East Asian (EAS) AF: 0.00 AC: 0 AN: 36610

South Asian (SAS) AF: 0.00 AC: 0 AN: 80618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088018

Other (OTH) AF: 0.00 AC: 0 AN: 58702

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.81	D
PhyloP100		6.5
PrimateAI	Uncertain	0.64	T
Sift4G	Benign	0.15	T
Polyphen		0.21	B
Vest4		0.83
MVP		0.39
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.83
gMVP		0.86
Mutation Taster		=31/69	disease causing

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: rs1554900934; hg19: chr8-145740548;