8-144517703-G-T

Variant names:

• chr8-144517703-G-T
• rs794726912
• NM_004260.4:c.82C>A

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.82C>A​(p.Gln28Lys) variant causes a missense, splice region 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. 10/15 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. Q28R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RECQL4 NM_004260.4 missense, splice_region
• Scores: Splicing: ADA: 0.00004690
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.589
• 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, SUPPORTIVE Submitted by: Orphanet, G2P
• Rothmund-Thomson syndrome

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

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

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.08801943).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	NM_004260.4	MANE Select	c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	NP_004251.4	O94761
	RECQL4	NM_001413019.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	NP_001399965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RECQL4	ENST00000617875.6	TSL:1 MANE Select	c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	ENSP00000482313.2	O94761
	RECQL4	ENST00000621189.4	TSL:1	c.-1055C>A		5_prime_UTR	Exon 1 of 20	ENSP00000483145.1	A0A087X072
	RECQL4	ENST00000971710.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1235402 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 606352

African (AFR) AF: 0.00 AC: 0 AN: 24524

American (AMR) AF: 0.00 AC: 0 AN: 17632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20014

East Asian (EAS) AF: 0.00 AC: 0 AN: 26630

South Asian (SAS) AF: 0.00 AC: 0 AN: 59266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3554

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1003562

Other (OTH) AF: 0.00 AC: 0 AN: 50184

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

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	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Benign	0.011	T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.088	T
PhyloP100		0.59
PrimateAI	Pathogenic	0.82	D
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.068
MVP		0.75
GERP RS		1.5
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.10
gMVP		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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: rs794726912; hg19: chr8-145743087;