8-144513353-C-T

Variant names:

• chr8-144513353-C-T
• rs1368178192
• NM_004260.4:c.2328G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000617875.6(RECQL4):​c.2328G>A​(p.Met776Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,453,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M776V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: RECQL4 ENST00000617875.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82
• 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

ENSG00000265393 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000617875.6. 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.2328G>A	p.Met776Ile	missense	Exon 14 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.2328G>A	p.Met776Ile	missense	Exon 14 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2328G>A	p.Met776Ile	missense	Exon 14 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.2328G>A	p.Met776Ile	missense	Exon 14 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1257G>A	p.Met419Ile	missense	Exon 13 of 20	ENSP00000483145.1
	RECQL4	ENST00000534626.6	TSL:5	c.633+63G>A		intron	N/A	ENSP00000477457.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000868 AC: 2 AN: 230362 AF XY: 0.00000784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000952

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453512 Hom.: 0 Cov.: 47 AF XY: 0.00000691 AC XY: 5 AN XY: 723460

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111638

Other (OTH) AF: 0.00 AC: 0 AN: 60278

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Benign	0.87
DEOGEN2	Benign	0.27	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.75	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		5.8
PrimateAI	Uncertain	0.74	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.35
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.95
gMVP		0.55
Mutation Taster		=46/54	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: rs1368178192; hg19: chr8-145738736;