rs775127620

Variant names:

• chr8-144514047-G-A
• rs775127620
• NM_004260.4:c.1939C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-144514047-G-A
• chr8-144514047-G-C
• chr8-144514047-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001413019.1(RECQL4):​c.1939C>T​(p.Arg647Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000278 in 1,581,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign 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. R647H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RECQL4 NM_001413019.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.188
• Publications: 5 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: 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=0.16350853).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001413019.1. 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.1939C>T	p.Arg647Cys	missense	Exon 12 of 21	NP_004251.4
	RECQL4	NM_001413019.1		c.1939C>T	p.Arg647Cys	missense	Exon 12 of 20	NP_001399948.1
	RECQL4	NM_001413036.1		c.1939C>T	p.Arg647Cys	missense	Exon 12 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.1939C>T	p.Arg647Cys	missense	Exon 12 of 21	ENSP00000482313.2
	RECQL4	ENST00000621189.4	TSL:1	c.868C>T	p.Arg290Cys	missense	Exon 11 of 20	ENSP00000483145.1
	RECQL4	ENST00000971710.1		c.1846C>T	p.Arg616Cys	missense	Exon 12 of 21	ENSP00000641769.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152096 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.0000105 AC: 2 AN: 189984 AF XY: 0.00

Gnomad AFR exome AF: 0.0000953

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: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 40 AN: 1429058 Hom.: 0 Cov.: 36 AF XY: 0.0000297 AC XY: 21 AN XY: 708254

African (AFR) AF: 0.0000306 AC: 1 AN: 32688

American (AMR) AF: 0.00 AC: 0 AN: 39818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25486

East Asian (EAS) AF: 0.0000266 AC: 1 AN: 37656

South Asian (SAS) AF: 0.00 AC: 0 AN: 82178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

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

European-Non Finnish (NFE) AF: 0.0000337 AC: 37 AN: 1096906

Other (OTH) AF: 0.0000169 AC: 1 AN: 59218

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152096 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

African (AFR) AF: 0.0000483 AC: 2 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

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

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Baller-Gerold syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.066	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.16	T
PhyloP100		0.19
PrimateAI	Benign	0.28	T
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.37
MVP		0.68
GERP RS		0.54
PromoterAI		-0.010	Neutral
Varity_R		0.16
gMVP		0.56
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775127620; hg19: chr8-145739431;