rs767220757

Variant names:

• chr8-144512481-A-C
• rs767220757
• NM_004260.4:c.2966T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-144512481-A-C
• chr8-144512481-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004260.4(RECQL4):​c.2966T>G​(p.Met989Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,612,278 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M989I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RECQL4 NM_004260.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.53
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2966T>G	p.Met989Arg	missense	Exon 17 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.3041T>G	p.Met1014Arg	missense	Exon 16 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.2966T>G	p.Met989Arg	missense	Exon 17 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.2966T>G	p.Met989Arg	missense	Exon 17 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.1895T>G	p.Met632Arg	missense	Exon 16 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.2873T>G	p.Met958Arg	missense	Exon 17 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 34

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000243 AC: 6 AN: 246434 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460086 Hom.: 0 Cov.: 66 AF XY: 0.0000220 AC XY: 16 AN XY: 726284

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51954

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152192 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000332 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	Uncertain	0.53
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.64
DEOGEN2	Benign	0.077	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.59	D
MutationAssessor	Benign	1.0	L
PhyloP100		8.5
PrimateAI	Benign	0.30	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.14	B
Vest4		0.36
MVP		0.42
GERP RS		5.3
PromoterAI		-0.012	Neutral
Varity_R		0.83
gMVP		0.74
Mutation Taster		=54/46	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: rs767220757; hg19: chr8-145737864;