8-144512237-T-C

Variant names:

• chr8-144512237-T-C
• rs202203322
• NM_004260.4:c.3143A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004260.4(RECQL4):​c.3143A>G​(p.Lys1048Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,612,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1048E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: -1.12
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015715122).

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.3143A>G	p.Lys1048Arg	missense	Exon 18 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.3218A>G	p.Lys1073Arg	missense	Exon 17 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.3143A>G	p.Lys1048Arg	missense	Exon 18 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.3143A>G	p.Lys1048Arg	missense	Exon 18 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.2072A>G	p.Lys691Arg	missense	Exon 17 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.3050A>G	p.Lys1017Arg	missense	Exon 18 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.000408 AC: 62 AN: 152134 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000241

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: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000437 AC: 108 AN: 247156 AF XY: 0.000452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.000373

Gnomad NFE exome AF: 0.000816

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000384 AC: 560 AN: 1460032 Hom.: 0 Cov.: 68 AF XY: 0.000416 AC XY: 302 AN XY: 726296

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000654 AC: 34 AN: 52022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000456 AC: 507 AN: 1111648

Other (OTH) AF: 0.000182 AC: 11 AN: 60340

GnomAD4 genome AF: 0.000408 AC: 62 AN: 152134 Hom.: 0 Cov.: 36 AF XY: 0.000417 AC XY: 31 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000707 Hom.: 1

Bravo AF: 0.000355

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000715 AC: 6

ExAC AF: 0.000499 AC: 60

EpiCase AF: 0.000818

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Baller-Gerold syndrome (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	1	-	RECQL4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.025
DANN	Benign	0.52
DEOGEN2	Benign	0.0079	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.016	T
MutationAssessor	Benign	-0.30	N
PhyloP100		-1.1
PrimateAI	Benign	0.35	T
Sift4G	Benign	0.84	T
Polyphen		0.0010	B
Vest4		0.050
MVP		0.77
GERP RS		-11
Varity_R		0.055
gMVP		0.47
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs202203322; hg19: chr8-145737620;